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PRODUCT MONOGRAPH Pr OMNITROPE TM somatropin [rDNA origin] for injection Lyophilized Powder for Injection: 5.8 mg/vial Solution for Injection: 5 mg/1.5 mL, 10 mg/1.5 mL Pharmaceutical Standard: Ph.Eur./USP Human Growth Hormone Sandoz Canada Inc. 145 Jules-Léger Boucherville, QC J4B 7K8 Date of Authorization: April 20, 2009 Submission Control No: 113380 OMNITROPE (somatropin for injection) Page 1 of 54 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION ........................................................................................ 3 SUMMARY PRODUCT INFORMATION .............................................................................................................. 3 DESCRIPTION......................................................................................................................................................... 3 INDICATIONS AND CLINICAL USE .................................................................................................................... 4 CONTRAINDICATIONS......................................................................................................................................... 4 WARNINGS AND PRECAUTIONS........................................................................................................................ 5 ADVERSE REACTIONS ......................................................................................................................................... 8 DRUG INTERACTIONS........................................................................................................................................ 14 DOSAGE AND ADMINISTRATION .................................................................................................................... 15 OVERDOSAGE...................................................................................................................................................... 17 ACTION AND CLINICAL PHARMACOLOGY................................................................................................... 17 STORAGE AND STABILITY................................................................................................................................ 24 DOSAGE FORMS, COMPOSITION AND PACKAGING.................................................................................... 24 PART II: SCIENTIFIC INFORMATION .............................................................................................................. 26 PHARMACEUTICAL INFORMATION ............................................................................................................... 26 CLINICAL TRIALS ............................................................................................................................................... 27 DETAILED PHARMACOLOGY........................................................................................................................... 41 TOXICOLOGY....................................................................................................................................................... 42 REFERENCES........................................................................................................................................................ 45 PART III: CONSUMER INFORMATION (LYOPHILIZED POWDER) .......................................................... 46 PART III: CONSUMER INFORMATION (SOLUTION FOR INJECTION) .................................................... 50 OMNITROPE (somatropin for injection) Page 2 of 54 Pr OMNITROPE TM Somatropin for Injection PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Subcutaneous injection Dosage Form/Strength Clinically Relevant Nonmedicinal Ingredients Lyophilized powder: 5.8 mg/vial 5.8 mg/vial: supplied with diluent containing 1.5% benzyl alcohol as preservative. 5 mg/1.5 mL: mannitol, benzyl alcohol (as Solution: preservative) 5 mg/1.5 mL (3.3 mg/mL) 10 mg/1.5 mL: phenol (as preservative) and 10 mg/1.5 mL (6.7 mg/mL) *For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section. Subcutaneous injection DESCRIPTION Omnitrope (somatropin for injection) is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues and a molecular weight of 22,125 daltons. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin (somatropin). Omnitrope is synthesized in a strain of Escherichia coli which has been modified by the addition of the human growth hormone gene. Omnitrope comes in two dosage forms: a sterile, white lyophilized powder and a clear, colourless, sterile solution both intended for subcutaneous injection. OMNITROPE (somatropin for injection) Page 3 of 54 INDICATIONS AND CLINICAL USE Pediatric Indication Omnitrope (somatropin for injection) is indicated for: • Growth Hormone Deficiency (GHD) in Children: Long-term treatment of children with growth failure due to an inadequate secretion of endogenous growth hormone. Other causes of short stature should be excluded. Adult Indication Omnitrope (somatropin for injection) is indicated for: • Adult Growth Hormone Deficiency (GHD): Long-term replacement therapy in adults with growth hormone deficiency due to underlying hypothalamic or pituitary disease or who were growth deficient during childhood. Growth hormone deficiency should be confirmed by an appropriate growth hormone stimulation test. Patients who were diagnosed as growth hormone deficient during childhood must be retested before treatment starts. Geriatrics (> 65 years of age): The safety and efficacy of Omnitrope in patients aged 65 and over has not been evaluated in clinical studies. Pediatrics (< 3 years of age): The safety and efficacy of Omnitrope in pediatric patients under the age of 3 years has not been evaluated in clinical studies. CONTRAINDICATIONS Omnitrope (somatropin for injection) should not be used when there is any evidence of neoplastic activity. Intracranial lesions must be inactive and antitumour therapy complete prior to the institution of therapy. Treatment with Omnitrope should be discontinued if there is evidence of tumour growth. Omnitrope should not be used for growth promotion in pediatric patients with closed epiphyses. Omnitrope should not be used in patients with acute critical illness following cardiac surgery, abdominal surgery, multiple trauma, or acute respiratory failure. Clinical studies demonstrated that high doses of another somatropin, were associated with a significantly increased morbidity and mortality in those patients.(see WARNINGS AND PRECAUTIONS). Growth hormone is contraindicated in patients with Prader-Willi Syndrome who are severely obese or have severe respiratory impairment (see WARNINGS AND PRECAUTIONS). OMNITROPE (somatropin for injection) Page 4 of 54 Omnitrope 5.8 mg/vial lyophilized powder when reconstituted with the diluent Bacteriostatic Water for Injection (benzyl alcohol preserved) and Omnitrope 5.0 mg/1.5 mL solution which also contains the preservative benzyl alcohol, should not be administered in newborns or in patients with a known sensitivity to benzyl alcohol (see WARNINGS AND PRECAUTIONS). Omnitrope is contraindicated in patients who are hypersensitive to somatropin or to any ingredient in the formulations. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph. WARNINGS AND PRECAUTIONS Serious Warnings and Precautions • • There have been reports of fatalities associated with the use of growth hormone in pediatric patients with Prader-Willi syndrome who have one or more of the following risk factors: severe obesity, history of respiratory impairment or sleep apnea or unidentified respiratory infection ( See WARNINGS AND PRECAUTIONS - CONGENITAL DISORDERS). Patients with acute critical illness suffering complications following open-heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure or similar conditions should not be treated with somatropin (See WARNINGS AND PRECAUTIONS - PERIOPERATIVE CONSIDERATIONS). GENERAL Treatment with Omnitrope (somatropin for injection), as with other growth hormone preparations, should be directed by physicians who are experienced in the diagnosis and management of patients with growth hormone deficiency. Patients and caregivers who will administer Omnitrope in medically unsupervised situations should receive appropriate training and instruction on the proper use of Omnitrope from the physician or other suitably qualified health professionals. CARCINOGENESIS AND MUTAGENESIS Mutagenicity or carcinogenicity studies have not been conducted with Omnitrope. CONGENITAL DISORDERS Prader-Willi Syndrome (see CONTRAINDICATIONS): There have been reports of fatalities after initiating therapy with growth hormone in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified infection. Male patients with one or more of these factors may be at greater risk than females. OMNITROPE (somatropin for injection) Page 5 of 54 ENDOCRINE AND METABOLISM For patients with diabetes mellitus, caution should be used if growth hormone is administered and insulin dosage may need to be adjusted when Omnitrope is instituted. Patients with diabetes or glucose intolerance should be monitored closely during treatment with Omnitrope. Patients with risk factors for glucose intolerance, such as obesity or a family history of Type II diabetes, should be monitored closely as well. Growth hormone may induce a state of insulin resistance, therefore patients should be observed for evidence of glucose intolerance. In patients with hypopituitarism (multiple hormonal deficiencies) standard hormonal replacement therapy should be monitored closely when treatment with Omnitrope is instituted. Hypothyroidism may develop during treatment with Omnitrope, and inadequate treatment of hypothyroidism may prevent optimal response to Omnitrope. Therefore, patients should have periodic thyroid function tests and be treated with thyroid hormone when indicated. HEMATOLOGIC Serum levels of inorganic phosphorous, alkaline phosphatase and Insulin-like Growth Factor 1 (IGF-1) may increase with growth hormone therapy. IMMUNE Local or systemic allergic reactions may occur. Parents and/or patients should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur. MUSCULOSKELETAL Pediatric patients with endocrine disorders, including growth hormone deficiency, have a higher incidence of slipped capital femoral epiphyses. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during growth hormone therapy should be evaluated. Progression of scoliosis can occur in patients who experience rapid growth. Because growth hormone increases growth rate, patients with a history of scoliosis who are treated with growth hormone should be monitored for progression of scoliosis. However, growth hormone has not been shown to increase the incidence of scoliosis. NEUROLOGIC Patients with growth hormone deficiency secondary to an intracranial lesion should be examined frequently for progression or recurrence of the underlying disease process. OMNITROPE (somatropin for injection) Page 6 of 54 Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with growth hormone products. Symptoms usually occurred within the first eight (8) weeks of the initiation of growth hormone therapy. In all reported cases, IH-associated signs and symptoms resolved after termination of therapy or a reduction of the growth hormone dose. Funduscopic examination of patients is recommended at the initiation, and periodically during the course of growth hormone therapy. PERIOPERATIVE CONSIDERATIONS See CONTRAINDICATIONS for information on increased mortality in patients with acute critical illnesses in intensive care units due to complications following open heart or abdominal surgery, multiple accidental traumas, or with acute respiratory failure. The safety of continuing growth hormone treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with growth hormone in patients having acute critical illnesses should be weighed against the potential risk. SENSITIVITY/RESISTANCE Patients with known sensitivities to benzyl alcohol should not use either the Omnitrope 5.8 mg/vial reconstituted with the Bacteriostatic Water for Injection diluent or the Omnitrope 5.0 mg/1.5 mL as both formulations contain benzyl alcohol. Sensitivity to Diluent: Benzyl alcohol has been associated with toxicity in newborns. The diluent, Bacteriostatic Water for Injection, for use with Omnitrope 5.8 mg/vial lyophilized powder contains benzyl alcohol as a preservative. Therefore, it should not be used in newborns. Omnitrope 5.0 mg/1.5 mL solution also contains the ingredient benzyl alcohol as a preservative. It must not be used in newborns. SPECIAL POPULATIONS Pregnant Women: Reproduction studies have not been conducted with Omnitrope. It is also not known whether Omnitrope can cause fetal harm when administered to a pregnant woman or affect reproduction capacity. Omnitrope should only be given to a pregnant woman if the benefits outweigh the risks. Nursing Women: There have been no studies conducted with Omnitrope in nursing mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Omnitrope is administered to a nursing woman. Pediatrics (< 3 years of age): The safety and efficacy of Omnitrope in pediatric patients under the age of 3 years has not been evaluated in clinical studies. Prudence is indicated for children under age of 3 years, when administering Omnitrope lyophilized powder reconstituted in Bacteriostatic Water for Injection (benzyl alcohol preserved) and Omnitrope 5.0 mg/1.5 mL solution (benzyl alcohol preserved); although there is no information on the toxicity of benzyl OMNITROPE (somatropin for injection) Page 7 of 54 alcohol for this age group, the toxic dose for premature neonates is in the range of 100 to 250 mg/kg per day. Adult Patients–Post-Pubertal GHD Patients: Before continuing treatment as an adult, a postpubertal growth hormone deficient patient who received growth hormone replacement therapy in childhood should be re-evaluated with proper testing as described in INDICATIONS AND CLINICAL USE. If continued treatment is appropriate, Omnitrope should be administered at the reduced dose level recommended for adults GHD patients. Geriatrics (>65 years of age): The safety and effectiveness of Omnitrope in patients aged 65 and over has not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of Omnitrope and may be more prone to develop adverse reactions. Renal or Hepatic Impairment: No studies have been conducted with Omnitrope in these patient populations. MONITORING AND LABORATORY TESTS See HEMATOLOGIC, ENDOCRINE AND METABOLISM, and MUSCULOSKELETAL sections. ADVERSE REACTIONS ADVERSE DRUG REACTION OVERVIEW Two serious adverse drug reactions (1%) on worsening of a preexisting scoliosis were reported in clinical trials with Omnitrope in the pediatric population. Most frequent adverse drug reactions (>5%) reported in clinical trials with Omnitrope Powder in the pediatric population were injection site reaction (12%), eosinophilia (9%) and headache (6%) Most frequent adverse drug reactions (>5%) reported in clinical trials with Omnitrope Solution in the pediatric population were glycosylated hemoglobin A1c (HbA1c) increased (9%), eosinophilia (7%) and injection site reaction (7%). Adverse drug reactions that most commonly result in clinical intervention with Omnitrope Powder in the pediatric population were hypothyroidism (3%) and headache (2%). Adverse drug reactions that most commonly resulted in clinical intervention with Omnitrope Solution in the pediatric population were headache (4%) and upper respiratory tract infections (2%). The following events were observed in patients using somatropins (see also WARNINGS AND PRECAUTION section: • Short-term local injection site reactions, such as pain, numbness, redness and swelling. The subcutaneous administration of growth hormone at the same injection site over a long period may result in local lipoatrophy. OMNITROPE (somatropin for injection) Page 8 of 54 • • • Disturbances in fluid balance (swelling), joint pain, muscle pain, stiffness of the hands and feet, numbness. In general, these undesirable effects occur at the beginning of therapy with growth hormones and also depend on the dose. They are common in adult patients, but uncommon in children. Carpal tunnel syndrome in adults. Benign intracranial hypertension, diabetes mellitus. Due to the content of benzyl alcohol in Omnitrope, rare general hypersensitivity reactions are possible. No case was observed during the clinical trials. Leukemia was reported in a small number of pediatric patients who were treated with growth hormone, including growth hormone of pituitary origin and recombinant growth hormone. The relationship, if any, between leukemia and growth hormone therapy is uncertain. CLINICAL TRIAL ADVERSE DRUG REACTIONS Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. ADVERSE DRUG REACTIONS REPORTED FROM OMNITROPE CLINICAL TRIALS As with all protein drugs, a small number of patients may develop antibodies to the protein. Growth hormone antibody with binding capacity lower than 2 mg/L has not been associated with growth attenuation. In some cases when binding capacity is >2 mg/L, interference with growth response has been observed. Preparations of Omnitrope contain a small amount of host cell Escherichia coli peptides (HCP). Anti-HCP antibodies are found in a small number of patients treated with Omnitrope, but these appear to be of no clinical significance. The following events were observed during the Omnitrope clinical studies conducted in children with growth hormone deficiency (GHD): OMNITROPE (somatropin for injection) Page 9 of 54 Most Common Adverse Drug Reactions (≥ 1%) for Omnitrope and Genotropin® Table 1a: Incidence of drug-related* adverse events occurring in ≥ 1% pediatric patients with GHD (Studies EP2K-99-PhIII/EP2K-00-PhIIIFo). Omnitrope Lyophilizate COV1 N=44 ® Genotropin N=45 Preferred Term N (%) N (%) Abdominal pain 1 (2%) 0 (0%) Anaemia 1 (2%) 0 (0%) Anorexia 1 (2%) 1 (2%) Arthralgia 1 (2%) 0 (0%) Coma 1 (2%) 0 (0%) Conjunctivitis 0 (0%) 1 (2%) Elevated HbA1c 4 (9%) 3 (7%) Eosinophilia 5 (11%) 3 (7%) Face oedema 1 (2%) 0 (0%) Fever 1 (2%) 0 (0%) Haematoma 4 (9%) 5 (11%) Headache 3 (7%) 3 (7%) Heart murmur 1 (2%) 0 (0%) Hypercholesterolaemia 1 (2%) 0 (0%) Hyperglycaemia 1 (2%) 0 (0%) Hypertriglyceridaemia 2 (5%) 2 (4%) Hypothyroidism 6 (14%) 2 (4%) Injection site pain 0 (0%) 1 (2%) Leg pain 1 (2%) 1 (2%) Pain 1 (2%) 0 (0%) Pharyngitis 0 (0%) 1 (2%) Polyuria 0 (0%) 1 (2%) Pruritus 1 (2%) 0 (0%) Purpura 0 (0%) 1 (2%) Scoliosis 0 (0%) 1 (2%) SGOT increased 0 (0%) 1 (2%) SGPT increased 0 (0%) 1 (2%) T4 decreased 0 (0%) 1 (2%) TSH decreased 0 (0%) 2 (4%) Vision abnormal 0 (0%) 1 (2%) *Drug-related = possible, probable or unclassified relationship to study drug N = number of patients 1=not marketed material OMNITROPE (somatropin for injection) Page 10 of 54 Table 1b: Incidence of drug-related* adverse events occurring in ≥ 1% pediatric patients with GHD (Study EP2K-00-PhIIIAQ Part A) Preferred Term Omnitrope lyophilizate N=44 Omnitrope liquid N=45 N (%) N (%) Arthralgia 0 (0%) 1 (2%) Bronchitis 0 (0%) 1 (2%) Elevated HbA1c 0 (0%) 3 (7%) Eosinophilia 2 (5%) 3 (7%) Haematoma 2 (5%) 1 (2%) Headache 2 (5%) 2 (4%) Hypercholesterolaemia 1 (2%) 1 (2%) Hypertriglyceridaemia 1 (2%) 1 (2%) Hypothyroidism 0 (0%) 1 (2%) Leg pain 1 (2%) 1 (2%) Scoliosis 0 (0%) 1 (2%) *Drug-related = possible, probable or unclassified relationship to study drug. N = number of patients. OMNITROPE (somatropin for injection) Page 11 of 54 Table1c: Incidence of drug-related* adverse events occurring in ≥ 1% pediatric patients with GHD (Study EP2K-00-PhIIIAQ Part B) Omnitrope liquid N=89 Preferred Term N (%) Bilirubinaemia 1 (1%) Convulsions 1 (1%) Elevated HbA1c 10 (11%) Endocrine disorder NOS 1 (1%) Eosinophilia 8 (9%) Haematoma 7 (8%) Headache 3 (3%) Hyperglycaemia 2 (2%) Hypertriglyceridaemia 1 (1%) Hypocholesterolaemia 1 (1%) Hypothyroidism 1 (1%) Leg pain 2 (2%) Leucopaenia 2 (2%) Leukocytosis 1 (1%) Pain 1 (1%) Phosphatase alkaline increased 4 (4%) Scoliosis 1 (1%) TSH decreased 2 (2%) *Drug-related = possible, probable or unclassified relationship to study drug. N = number of patients. OMNITROPE (somatropin for injection) Page 12 of 54 Table 1d: Incidence of drug-related* adverse events occurring in ≥ 1% pediatric patients with GHD (Studies EP2K-02-PhIII-Lyo and EP2K-00-PhIIIb-E) EP2K-02-PhIII-Lyo1 N=51 EP2K00PhIIIb-E2 N=50 Preferred Term N (%) N (%) Abdomnial pain 1 (2 %) 0 (0%) Antibody test abnormal 0 (0%) 2 (4 %) Arthralgia 1 (2 %) 0 (0%) Blood alkaline phosphatase increased 1 (2 %) 0 (0%) Contusion 1 (2 %) 0 (0%) Dermatitis 0 (0%) 1 (2 %) Eosinophilia 6 (12 %) 0 (0%) Fatigue 1 (2 %) 0 (0%) Fundoscopy abnormal 1 (2 %) 0 (0%) Glycosylated haemoglobin increased 1 (2 %) 0 (0%) Headache 4 (8 %) 1 (2 %) Hypothyroidism 4 (8 %) 0 (0%) Injection site erythema 1 (2 %) 0 (0%) Injection site haemorrhage 5 (10 %) 0 (0%) Injection site inflammation 1 (2 %) 0 (0%) Injection site oedema 1 (2 %) 0 (0%) Injection site pain 0 (0%) 1 (2 %) Injection site reaction 1 (2 %) 0 (0%) Lipodystrophy acquired 1 (2 %) 0 (0%) Migraine 0 (0%) 1 (2 %) Myopia 1 (2 %) 0 (0%) Nasopharyngitis 1 (2 %) 0 (0%) Neck pain 1 (2 %) 0 (0%) Pain in extremity 1 (2 %) 0 (0%) Pyrexia 1 (2 %) 0 (0%) Scoliosis 3 (6 %) 0 (0%) Tendonitis 0 (0%) 1 (2 %) Viral pharyngitis 0 (0%) 1 (2 %) Vomiting 0 (0%) 1 (2 %) *Drug-related = possible, probable or unclassified relationship to study drug. N = number of patients. 1= 24 months 2= up to 30 months OMNITROPE (somatropin for injection) Page 13 of 54 Less Common Clinical Trial Adverse Drug Reactions (<1%) The following list provides the incidence of drug-related adverse events occurring in pediatric patients with GHD (< 1%) - Hypothyroidism Scoliosis Arthralgia Hypercholesterolemia Hypertriglyceridemia Pharyngitis Pain Bronchitis Convulsions Endocrine disorders Bilirubinaemia Leucocytosis Vomiting Tendonitis Migraine Dermatitis Regarding the adverse drug reactions reported from somatropin products in adults, replacement therapy in growth hormone deficient adult patients is often accompanied by signs and symptoms of fluid retention, such as edema, arthralgia and paraesthesia. Musculo-skeletal pain and/or stiffness may also occur. These events usually have an early onset after initiation of treatment with a reduction in incidence and prevalence over time. In most cases the severity is mild or moderate. One patient developed diabetes mellitus during Genotropin® therapy, which was probably attributable to treatment. The following events were also reported infrequently: carpal tunnel syndrome; headache; back pain; myalgia; hypoesthesia. POSTMARKET ADVERSE DRUG REACTIONS The postmarketing data available for Omnitrope did not reveal any unexpected adverse drug reactions. DRUG INTERACTIONS DRUG-DRUG INTERACTIONS No studies on the interaction of Omnitrope with other drugs have been performed. Concomitant glucocorticoid treatment may inhibit the growth-promoting effect of human growth hormone. Pediatric growth hormone-deficient patients with coexisting Adrenocorticotropic Hormone (ACTH) deficiency should have their glucocorticoid replacement dose carefully adjusted to avoid an inhibitory effect on growth (see also WARNINGS AND PRECAUTIONS, ENDOCRINE AND METABOLISM). Limited published data indicate that growth hormone treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that growth hormone administration may alter the clearance of compounds known to be metabolized by CP450 liver OMNITROPE (somatropin for injection) Page 14 of 54 enzymes (e.g. corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when growth hormone is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. Table 2 - Established or Potential Drug-Drug Interactions with Omnitrope Therapeutic Class Glucocorticoids Effect Concomitant glucocorticoid treatment may inhibit the growth promoting effect of human growth hormone. Cytochrome P450 Somatropin may be an inducer of CP450 34A when administered in combination with metablized by CP450 liver enzymes. Clinical Comment Patients with coexisting ACTH deficiency should have their glucocorticoid replacement dose carefully adjusted to avoid an inhibitory effect on growth. Patients should be monitored for clinical effectiveness of such drugs. Legend: ACTH = Adrenocorticotropic Hormone DRUG-FOOD INTERACTIONS Interactions with food have not been established. DRUG-HERB INTERACTIONS Interactions with herbal products have not been established. DRUG-LABORATORY TEST INTERACTIONS Interactions with laboratory tests have not been established. DOSAGE AND ADMINISTRATION RECOMMENDED DOSE AND DOSAGE ADJUSTMENT The dosage and administration schedule of Omnitrope (somatropin for injection) should be individualized for each patient. The doses should be given by subcutaneous injections (administered preferably in the evening). Omnitrope may be given in the thigh, buttocks, or abdomen; the site of subcutaneous injections should be rotated daily to help prevent lipoatrophy. Growth disturbance in children due to inadequate endogenous growth hormone secretion: Generally a dose of 0.025–0.035 mg/kg body weight daily is recommended. Growth hormone deficiency in adult patients: The recommended starting dose is 0.15 - 0.3 mg/day. The final dose should be individually increased as required with respect to age and gender to a maximum daily maintenance dose of 1.33 mg. Women may require higher doses than men. As normal physiological growth hormone production decreases with age, dose requirements may be reduced. Clinical response, side effects and determination of IGF-1 in serum may be used as guidance for dose titration. The level of IGF-1 should not exceed the upper limit of normal IGF-1 levels matched to age and sex. OMNITROPE (somatropin for injection) Page 15 of 54 MISSED DOSE For patients who miss a dose of Omnitrope, it is not recommended to double the next dose. Administer the regular dose at the next scheduled dosage time. Patients should contact their physician for instructions. ADMINISTRATION Omnitrope (somatropin for injection) – Vials of 5.8 mg: Reconstitution Omnitrope (somatropin for injection) lyophilized powder is dispensed in vials of 5.8 mg: • A 5.8 mg vial of Omnitrope lyophilized powder should be reconstituted with 1.14 mL of Bacteriostatic Water for Injection (benzyl alcohol preserved). The concentration of the reconstituted solution is 5.0 mg/mL. After reconstitution, the solution may be refrigerated for a maximum of 28 days between 2 to 8°C. To prepare the Omnitrope solution, first disinfect both the rubber membrane of the vial and the cartridge containing diluent with an alcohol swab. Then, slowly inject the Bacteriostatic Water for Injection from the cartridge into the Omnitrope vial using the transfer set. Follow the directions that came with the transfer set. Gently swirl the reconstituted vial until the content is completely dissolved. Do not shake. After reconstitution, the Omnitrope solution should be clear. If the solution is cloudy or contains particles, it should not be used. Transfer all of the dissolved solution back into the cartridge using the transfer set. This presentation is intended for multiple use. It should only be administered with the Omnitrope Pen L, an injection device specifically developed for use with Omnitrope 5.0 mg/mL reconstituted solution for injection. The solutions must be administered using sterile, disposable pen needles. The solution must be clear. Do not inject if the solution is cloudy. Patients and caregivers must receive appropriate training and instruction on the proper use of the Omnitrope vials, diluent cartridge, transfer set and pen from the physician or other qualified healthcare professional. After reconstitution and first injection, the diluent cartridge should remain in the Pen L and be refrigerated between 2 to 8 °C. Omnitrope (somatropin for injection) – 5.0 mg/1.5 mL ; 10.0 mg/1.5 mL Cartridges Omnitrope 5.0 mg/1.5 mL and 10.0 mg/1.5 mL solutions for injection, are sterile, ready-to-use solutions filled in pen cartridges. Both presentations are indicated for multiple use. They should only be administered with the Omnitrope Pen 5 and Omnitrope Pen 10 pen injection devices specifically developed for use with Omnitrope 5.0 mg/1.5 mL and Omnitrope 10.0 mg/1.5 mL, respectively. The solutions must be administered using sterile, disposable pen needles. The solution must be clear prior to insertion of the cartridge into the Pen. Do not inject if the solution is cloudy. Patients and caregivers have to OMNITROPE (somatropin for injection) Page 16 of 54 receive appropriate training and instruction on the proper use of the Omnitrope cartridges and pens from the physician or other suitable qualified healthcare professionals. After the first injection, the content of the cartridge must be used within 28 days. The cartridge should remain in the pen and be refrigerated between 2 and 8°C. Do not freeze. Protect from light. The following is a general description of the administration process. The manufacturer’s instructions provided with the pens must be followed for loading the cartridge, attaching the injection needle and for the administration. Wash your hands. 1. Ensure that the solution in the cartridge is clear and colourless prior to inserting the cartridge into the Pen. Do not use if the solution is cloudy or contains particulate matter. 2. Disinfect the rubber membrane of the cartridge with an alcohol swab. 3. Insert the cartridge into the Omnitrope Pen following the instructions for use provided with the pen. 4. Clean the site of injection with an alcohol swab. 5. Administer the appropriate dose by subcutaneous injection using a sterile pen needle. The sites of injection should be rotated each time Omnitrope is administered to avoid lipoatrophy. 6. Remove the pen needle and dispose of it in accordance with local requirements. OVERDOSAGE There is little information on acute or chronic overdosage with Omnitrope. Intravenously administered growth hormone has been shown to result in an acute decrease in plasma glucose and subsequently to hyperglycemia. It is thought that the same effect might occur on rare occasions with high dosages of Omnitrope administered subcutaneously. Long-term overdosage may result in signs and symptoms of acromegaly, consistent with overproduction of human growth hormone. ACTION AND CLINICAL PHARMACOLOGY MECHANISM OF ACTION Omnitrope (somatropin for injection) is a human growth hormone (hGH) produced by recombinant DNA technology. The amino acid sequence of the somatropin protein is identical to that of the human growth hormone of pituitary origin. In vitro, preclinical, and clinical tests have demonstrated that somatropins are therapeutically equivalent to human growth hormone of pituitary origin and achieve similar pharmacokinetic profiles in normal adults. In pediatric patients who have growth hormone deficiency (GHD), treatment with somatropin stimulates linear growth and normalizes concentrations of Insulin-like Growth Factor -I (IGF-I). OMNITROPE (somatropin for injection) Page 17 of 54 In adults with GHD, treatment with somatropin results in reduced fat mass, increased lean body mass, metabolic alterations that include beneficial changes in lipid metabolism, and normalization of IGF-I concentrations. In addition, the following actions have been demonstrated for Omnitrope (somatropin for injection) and/or human growth hormone of pituitary origin. Tissue Growth • Skeletal Growth: Somatropin stimulates skeletal growth in children with growth failure due to inadequate secretion of endogenous growth hormone. The measurable increase in body length after administration of somatropin results from an effect on the epiphyseal plates of long bones. Concentrations of IGF-I, which may play a role in skeletal growth, are generally low in the serum of pediatric patients with growth hormone deficiency, but tend to increase during treatment with Omnitrope. Elevations in mean serum alkaline phosphatase concentration are also seen. • Cell Growth: It has been shown that there are fewer skeletal muscle cells in short-statured children who lack endogenous growth hormone as compared with the normal pediatric population. Treatment with somatropin for injection results in an increase in both the number and size of skeletal muscle cells. Protein Metabolism Linear growth is facilitated in part by increased cellular protein synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and serum urea nitrogen, follows the initiation of therapy with somatropin. Carbohydrate Metabolism Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia, which is improved by treatment with somatropin. Large doses of growth hormone may impair glucose tolerance. Lipid Metabolism In growth hormone-deficient patients, administration of recombinant somatropin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids. Mineral Metabolism Retention of sodium, potassium, and phosphorus is induced by pituitary growth hormone in children. Serum concentrations of inorganic phosphate are increased in patients with growth hormone deficiency after therapy with somatropin. Serum calcium is not significantly altered in patients treated with somatropin. Growth hormone could increase calciuria. Body Composition Adult growth hormone-deficient patients treated with somatropin at the recommended adult dose (see DOSAGE AND ADMINISTRATION) demonstrate a decrease in fat mass and an increase OMNITROPE (somatropin for injection) Page 18 of 54 in lean body mass. When these alterations are coupled with the increase in total body water, the overall effect of somatropin is to modify body composition, an effect that is maintained with continued treatment. Pharmacodynamics Table 3. Pharmacodynamic Parameters after a Single SC Administration of 5 mg Omnitrope Powder for Solution for Injection (5.8mg/vial) and of 5 mg Omnitrope 10.0 mg/1.5 mL Solution for Injection IGF-1 AUEClast [h·µg/L] Emax [µg/L] tmax,E [h] 5mg of Omnitrope powder for solution for injection; 5.8 mg/vial (N = 32) 20355 ± 5067 267 ± 64 24* (16 - 48) 5mg of Omnitrope 10.0 mg/1.5 mL solution for injection (N = 32) 19829 ± 5107 265 ± 68 24* (16 - 24) Results are presented as mean ± SD. *median value (min - max) for tmax,E Legend: IGF-1 = Insulin-like Growth Factor 1 OMNITROPE (somatropin for injection) Page 19 of 54 IGFBP-3 AUEClast [h·mg/L] Emax [mg/L] tmax,E [h] 5mg of Omnitrope powder for solution for injection; 5.8 mg/vial (N = 32) 471 ± 70 5.4 ± 0.8 48* (16 – 96) 5mg of Omnitrope 10.0 mg/1.5 mL solution for injection (N = 32) 468 ± 67 5.4 ± 0.8 48* (0 - 72) Results are presented as mean ± SD. *median value (min - max) for tmax,E Legend: IGFBP = Insulin-like Growth Factor Binding Protein 3 NEFA AUEClast [h·mmol/L] Emax [mmol/L] tmax,E [h] 5mg of Omnitrope powder for solution for injection; 5.8 mg/vial (N = 32) 13.1 ± 3.8 1.1 ± 0.3 3* (1 - 16) 5mg of Omnitrope 10.0 mg/1.5 mL solution for injection (N = 32) 12.8 ± 3.7 1.1 ± 0.3 3* (2 - 16) Results are presented as mean ± SD. *median value (min - max) for tmax,E Legend: NEFA = Nonesterified Fatty Acids Table 4. Pharmacodynamic Parameters after a Single SC Administration of 5 mg Omnitrope Powder for Solution for Injection (5.8mg/vial) and of 5mg Omnitrope 5.0 mg/1.5 mL Solution for Injection IGF-1 AUEClast [h·µg/L] Emax [µg/L] tmax,E [h] 5mg of Omnitrope powder for solution for injection; 5.8 mg/vial (N = 35) 16712 ± 3847 218 ± 56 24* (12 - 48) 5mg of Omnitrope 5.0 mg/1.5 mL solution for injection (N = 35) 16295 ± 3664 213 ± 49 24* (12 - 48) Results are presented as mean ± SD. *median value (min - max) for tmax,E OMNITROPE (somatropin for injection) Page 20 of 54 IGFBP-3 AUEClast [h·mg/L] Emax [mg/L] tmax,E [h] 5mg of Omnitrope powder for solution for injection; 5.8 mg/vial (N = 35) 430 ± 61 4.9 ± 0.7 48* (24 – 96) 5mg of Omnitrope 5.0 mg/1.5 mL solution for injection (N = 35) 427 ± 56 4.9 ± 0.6 48* (12 - 96) Results are presented as mean ± SD. *median value (min - max) for tmax,E NEFA AUEClast [h·mmol/L] Emax [mmol/L] tmax,E [h] 5mg of Omnitrope powder for solution for injection; 5.8 mg/vial (N = 35) 15.3 ± 4.9 1.3 ± 0.3 2* (0 - 16) 5mg of Omnitrope 5.0 mg/1.5 mL solution for injection (N = 35) 14.8 ± 3.8 1.2 ± 0.3 2* (1 - 24) Results are presented as mean ± SD. *median value (min - max) for tmax,E OMNITROPE (somatropin for injection) Page 21 of 54 Pharmacokinetics Table 5. Pharmacokinetic Parameters After a Single SC Administration of 5 mg of Omnitrope Powder for Solution for Injection (5.8mg/vial) and 5 mg of Omnitrope 10.0 mg/1.5 mL Solution for Injection AUCT [h·µg/L] AUCI [h·µg/L] Cmax [µg/L] tmax [h] t1/2 [h] 5mg of Omnitrope powder for solution for injection; 5.8 mg/vial (N = 32) 550 ± 96 555 ± 96 69 ± 16 4.0* (2.0 - 6.0) 2.9 ± 0.5 5 mg of Omnitrope 10.0 mg/1.5 mL solution for injection (N = 32) 558 ± 115 561 ± 114 74 ± 22 4.0* (2.0 - 6.0) 2.5 ± 0.7 Results are presented as mean ± SD . *median value (min - max) Table 6. Pharmacokinetic Parameters After a Single SC Administration of 5 mg of Omnitrope Powder for Solution for Injection (5.8 mg/vial)and 5 mg of Omnitrope 5.0 mg/1.5 mL Solution for Injection AUCT [h·µg/L] AUCI [h·µg/L] Cmax [µg/L] tmax [h] t1/2 [h] 5 mg of Omnitrope powder for solution for injection; 5.8 mg/vial (N = 35) 559 ± 148 566 ± 147 71 ± 24 4.0* (2.0 -6.0) 3.2 ± 0.7 5 mg of Omnitrope 5.0 mg/1.5 mL solution for injection (N = 35) 542 ± 141 546 ± 140 72 ± 28 4.0* (2.0 -8.0) 2.8 ± 0.7 Results are presented as mean ± SD (n=35). * median value (min - max) For additional information on comparative pharmacokinetic and pharmacodynamic studies please refer to “CLINICAL TRIALS” of PART II. Absorption The bioavailability of subcutaneously administered somatropin is approximately 80% in both healthy subjects and growth hormone deficient patients. A subcutaneous dose of 5 mg of Omnitrope (5.0 mg/1.5 mL Solution for Injection) in healthy adults results in plasma Cmax and OMNITROPE (somatropin for injection) Page 22 of 54 tmax values of 72 ± 28 mcg/L and 4.0 ± 2.0 hours, respectively. Following SC injection, maximum serum growth hormone concentrations are reached approximately 4 hours (range 2 to 8 hours) and growth hormone serum concentrations return to baseline within 24 hours. Elimination The mean terminal half-life of somatropin after intravenous administration in growth hormone deficient adults is about 0.4 hours. However, after subcutaneous administration of Omnitrope in healthy adults, a half-life of approximately 3 hours is estimated. The longer half-life observed after subcutaneous administration is an example of ‘flip-flop’ pharmacokinetics, such that the estimated elimination rate is actually the absorption rate from the site of administration. The mean metabolic clearance of Omnitrope, subcutaneously administered in healthy adults, is 0.14 (± 0.04) L/hr⋅kg. Metabolism Extensive metabolism studies have not been conducted. The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys. Subpopulations The absolute bioavailability of somatropin seems to be similar in males and females following subcutaneous administration. Information about the pharmacokinetics of somatropin in geriatric and pediatric populations, in different races and in patients with renal, hepatic or cardiac insufficiency is either lacking or incomplete. SPECIAL POPULATIONS AND CONDITIONS Pediatrics: No studies to estimate recombinant human Growth Hormone (rhGH) clearance have been conducted with Omnitrope in these patient populations. Gender: No gender studies have been performed in pediatric patients; however, following a subcutaneous injection of 5 mg Omnitrope to healthy adult volunteers, gender had no effect on the pharmacokinetic parameters of Omnitrope (Cmax and tmax). Race: No studies have been conducted with Omnitrope to assess pharmacokinetic differences among races. Elderly, Renal, Hepatic or Cardiac Insufficiency: No studies have been conducted with Omnitrope in these patient populations. OMNITROPE (somatropin for injection) Page 23 of 54 STORAGE AND STABILITY OMNITROPE (SOMATROPIN FOR INJECTION) 5.8 mg/vial: Before Reconstitution: Vials of Omnitrope (somatropin for injection) and the supplied diluent for Omnitrope are stable when stored at 2 to 8 °C. Avoid freezing the diluent for Omnitrope. Expiration dates are stated on the labels. After Reconstitution: Omnitrope 5.8 mg/vial is supplied with the diluent, Bacteriostatic Water for Injection containing 1.5% benzyl alcohol as a preservative. After reconstitution, the contents of the vial must be used within 28 days and refrigerated between 2 and 8°C. The cartridge containing the reconstituted Omnitrope solution should remain in the Pen L and also refrigerated between 2 and 8°C. Refrigerate Omnitrope between 2 and 8°C . Do not freeze. Omnitrope is light sensitive and should be stored in the carton. OMNITROPE (SOMATROPIN FOR INJECTION) 5.0 mg/ 1.5 mL, 10.0 mg/1.5 mL: Omnitrope pen cartridges for use with Pen 5 and Pen 10. • • • • • • • • Keep out of reach and sight of children. Store in the original package in order to protect from light. Store between 2 and 8°C (in a refrigerator). Do not freeze. Use a cool box for transporting the package(s) if you are travelling. After the first injection, the cartridge should remain in the pen injector and has to be kept in a refrigerator between 2°C to 8°C for a maximum of 28 days (see Instructions for Use of the pen injector). Do not use after the expiry date stated on the label and carton. Do not use Omnitrope if it was frozen or subject to high temperatures. Do not use Omnitrope if you notice that the solution is cloudy or contains particles. DOSAGE FORMS, COMPOSITION AND PACKAGING DOSAGE FORM AND COMPOSITION Omnitrope (somatropin for injection) is a sterile lyophilized powder in vials for reconstitution: • 5.8 mg Vial: Each vial contains 5.8 mg somatropin (approximately 17.4 IU), 27.6 mg glycine, 2.09 mg disodium hydrogen phosphate heptahydrate and 0.56 mg sodium dihydrogen phosphate dihydrate. • Diluent: The 5.8 mg vial is supplied with a cartridge containing 1.14 mL of diluent (Bacteriostatic Water for Injection containing 1.5% benzyl alcohol as a preservative). After reconstitution, the solution has a concentration of 5.0 mg/mL (approximately 15 IU/mL). OMNITROPE (somatropin for injection) Page 24 of 54 Omnitrope Pen Cartridges contain somatropin solution for injection: • 5.0 mg/1.5 mL Cartridge: Each 1.5 mL pen cartridge contains: 5.0 mg of somatropin (15 IU/1.5 mL), 1.3 mg disodium hydrogen phosphate heptahydrate, 1.6 mg sodium dihydrogen phosphate dihydrate, 3.0 mg poloxamer 188, 13.5 mg benzyl alcohol, 52.5 mg mannitol and water for injection. Phosphoric acid and/or sodium hydroxide may have been used to adjust pH. • 10.0 mg/1.5 mL Cartridge: Each 1.5 mL pen cartridge contains: 10.0 mg of somatropin (30.0 IU/1.5 mL), 1.70 mg disodium hydrogen phosphate heptahydrate, 1.35 mg sodium dihydrogen phosphate dihydrate, 3.0 mg poloxamer 188, 4.5 mg phenol, 27.75 mg gylcine and water for injection. Phosphoric acid and/or sodium hydroxide may have been used to adjust pH. PACKAGING Omnitrope Lyophilized Powder is supplied as: Omnitrope 5.8 mg/vial: Carton contains 8 vials of Omnitrope 5.8 mg and 8 cartridges of diluent (Bacteriostatic Water for Injection containing 1.5% benzyl alcohol as a preservative.) Omnitrope Pen Cartridge is supplied as: Omnitrope 5.0 mg/1.5 mL is supplied in the following pack sizes: • One cartridge per carton • Five cartridges per carton • Ten cartridges per carton Omnitrope 10.0 mg/1.5 mL is supplied in the following pack sizes: • One cartridge per carton • Five cartridges per carton • Ten cartridges per carton OMNITROPE (somatropin for injection) Page 25 of 54 PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION DRUG SUBSTANCE Proper name: Somatropin Common name: recombinant human growth hormone (rhGH) Molecular formula: C990H1528N262O300S7 (191 amino acid residues) Molecular mass: 22,125 daltons Structural formula: Physicochemical properties: Biological Activity OMNITROPE (somatropin for injection) The biological activity of growth hormone is approximately 3.0 international units/1 mg. Page 26 of 54 CLINICAL TRIALS Comparative Pharmacokinetic and Pharmacodynamic Studies During the clinical development of the lyophilized powder and the liquid formulations of Omnitrope, five clinical pharmacology studies, EP2K-99-PhISUSA, EP2K-99-PhIUSA EP2K-00-PhIAQ, EP00-104 and EP00-105, were performed in healthy volunteers after a single subcutaneous dose of 5 mg. Four of these Phase I studies were comparative bioavailability studies. Pharmacokinetics The results for the pharmacokinetic parameters of the Growth Hormone (GH) concentrations determined during the four comparative Phase I studies are summarized in the tables below. Table 7. Pharmacokinetic Parameters after a Single SC Administration of 5 mg Omnitrope Powder for Solution for Injection (5.8 mg/vial) and of 5 mg Genotropin® 5 mg/mL Powder for Solution for Injection – Study EP2K-99-PhIUSA AUCT [h·µg/L] AUCI [h·µg/L] Cmax [µg/L] tmax* [h] t1/2 [h] 5 mg of Omnitrope powder for solution for injection; 5.8 mg/vial (N = 24) 413 ± 111 416 ± 110 52 ± 21 4 (2 - 8) 2.7 ± 0.6 5 mg of Genotropin® 5 mg/mL powder for solution for injection (N = 24) 396 ± 106 400 ± 105 48 ± 20 4 (2 - 10) 2.9 ± 0.6 Ratio and 90% confidence interval [%] (N = 24) 104.18 [99.97 ; 108.58] 104.00 [99.90 ; 108.27] 106.96 [97.96 ; 116.78] Results are presented as mean ± SD. *median value (min - max) for tmax OMNITROPE (somatropin for injection) Page 27 of 54 Table 8. Pharmacokinetic Parameters after a Single SC Administration of 5 mg Omnitrope 5 mg/1.5 mL Solution for Injection and of 5 mg Omnitrope Powder for Solution for Injection (5.8 mg/vial) – Study EP2K00-PhIAQ 5 mg of Omnitrope 5 mg/1.5 mL solution for injection (N = 24) 422 ± 45 426 ± 45 52 ± 10 3 (2 - 8) 2.4 ± 0.7 AUCT [h·µg/L] AUCI [h·µg/L] Cmax [µg/L] tmax* [h] t1/2 [h] 5 mg of Omnitrope powder for solution for injection; 5.8 mg/vial (N = 24) 453 ± 43 456 ± 44 55 ± 13 3 (2 - 10) 2.4 ± 0.6 Ratio and 90% confidence interval [%] (N = 24) 93.13 [89.89 ; 96.48] 93.32 [90.10 ; 96.65] 94.76 [90.29 ; 99.45] Results are presented as mean ± SD. *median value (min - max) for tmax OMNITROPE (somatropin for injection) Page 28 of 54 Table 9. Pharmacokinetic Parameters after a Single SC Administration of 5 mg Omnitrope 5 mg/1.5 mL Solution for Injection, of 5 mg Omnitrope Powder for Solution for Injection (5.8 mg/vial), and of 5 mg Genotropin® 5 mg/mL Powder for Solution for Injection – Study EP00-104 AUCT [h·µg/L] AUCI[h·µg/L] Cmax [µg/L] tmax* [h] t1/2 [h] Ratio of LS-Means and 90% CI [%] 5 mg of Omnitrope powder for solution for injection; 5.8 mg/vial (N = 35) 559 ± 148 566 ± 147 71 ± 24 4 (2 - 6) 3.2 ± 0.7 5 mg of Omnitrope 5.0 mg/1.5 mL solution for injection (N = 35) 5 mg of Genotropin® 5 mg/mL powder for solution for injection (N = 35) 542 ± 141 546 ± 140 72 ± 28 4 (2 - 8) 2.8 ± 0.7 588 ± 133 592 ± 131 78 ± 27 4 (2 - 8) 2.6 ± 0.7 AUCT: 103.58 [98.86 ; 108.52] AUCI: 103.90 [99.23 ; 108.78] Cmax: 102.15 [94.28 ; 110.68] AUCT: 94.20 [89.90 ; 98.69] AUCI: 94.67 [90.42 ; 99.12] Cmax: 91.57 [84.51 ; 99.22] AUCT: 90.94 [86.80 ; 95.29] AUCI: 91.12[87.03 ; 95.40] Cmax: 89.64 [82.73 ; 97.12] Results are presented as mean ± SD. *median value (min - max) for tmax OMNITROPE (somatropin for injection) Page 29 of 54 Table 10. Pharmacokinetic Parameters after a Single SC Administration of 5 mg Omnitrope 10 mg/1.5 mL Solution for Injection, of 5 mg Omnitrope Powder for Solution for Injection (5.8 mg/vial), and of 5 mg Genotropin® 5 mg/mL Powder for Solution for Injection – Study EP00-105 AUCT [h·µg/L] AUCI [h·µg/L] Cmax [µg/L] tmax* [h] t1/2 [h] Ratio of LS-Means and 90% CI [%] 5 mg of Omnitrope powder for solution for injection; 5.8 mg/vial (N = 32) 550 ± 96 555 ± 96 69 ± 16 4 (2 - 6) 2.9 ± 0.5 5 mg of Omnitrope 10 mg/1.5 mL solution for injection (N = 32) 5 mg of Genotropin® 5 mg/mL powder for solution for injection (N = 32) 558 ± 115 561 ± 114 74 ± 22 4 (2 - 6) 2.5 ± 0.7 537 ± 110 540 ± 110 73 ± 20 4 (2 - 6) 2.5 ± 0.7 AUCT: 98.70 [95.54 ; 101.96] AUCI: 98.81 [95.64 ; 102.09] Cmax: 95.28 [90.59 ; 100.22] AUCT: 102.27 [99.03 ; 105.62] AUCI: 102.28 [99.03 ; 105.64] Cmax: 95.89 [91.22 ; 100.81] AUCT: 103.62 [100.34 ; 107.01] AUCI: 103.51 [100.22 ; 106.91] Cmax: 100.64 [95.74 ; 105.80] Results are presented as mean ± SD. *median value (min - max) for tmax After single doses of 5 mg of Omnitrope are administered via SC route, bioequivalence was demonstrated among the different formulations and strengths of Omnitrope products. Bioavailability of Omnitrope lyophilized powder 5.8 mg/Vial, solution for injection 5 mg/1.5 mL and solution for injection 10 mg/1.5mL are comparable to that of Genotropin® 5.8 mg (5 mg/mL) at the same dose administered via the same route in adult healthy volunteers. Pharmacodynamics The results for the pharmacodynamic parameters IGF-1, IGFBP-3, and NEFA determined during the four comparative Phase I studies are summarized in the tables below. OMNITROPE (somatropin for injection) Page 30 of 54 Table 11. Pharmacodynamic Parameters after a Single SC Administration of 5 mg Omnitrope Powder for Solution for Injection (5.8mg/vial) and of 5 mg Genotropin® 5 mg/mL Powder for Solution for Injection – Study EP2K-99-PhIUSA IGF-1 IGFBP-3 NEFA AUEC [h·µg/L] Emax [µg/L] tmax,E* [h] AUEC [h·mg/L] Emax [mg/L] tmax,E* [h] AUEC [h·mmol/L] Emax [mmol/L] tmax,E* [h] 5 mg of Omnitrope powder for solution for injection; 5.8 mg/vial (N = 24) 31974 ± 10766 458 ± 159 24 (12 - 97) 5 mg of Genotropin® 5 mg/mL powder for solution for injection (N = 24) 420 ± 124 5.6 ± 2.1 24 (0 - 97) 431 ± 148 5.3 ± 1.9 48 (0 - 97) 98.55 [90.72; 107.06] 103.83 [94.99; 113.49] 10.4 ± 4.2 1.0 ± 0.2 4 (3 - 8) 10.7 ± 4.0 1.0 ± 0.3 4 (3 - 12) 97.44 [84.00; 113.04] 102.02 [89.50; 116.30] 29893 ± 9569 428 ± 152 24 (12 - 96) Ratio and 95% confidence interval [%] (N = 24) 106.11 [97.18; 115.86] 106.58 [92.51; 122.80] Results are presented as mean ± SD. *median value (min - max) for tmax,E Table12. Pharmacodynamic Parameters after a Single SC Administration of 5 mg Omnitrope 5 mg/1.5 mL Solution for Injection and of 5 mg Omnitrope Powder for Solution for Injection (5.8 mg/vial) – Study EP2K00-PhIAQ 19087 ± 4684 264 ± 58 24 (12 - 24) 5 mg of Omnitrope powder for solution for injection; 5.8 mg/vial (N = 24) 18806 ± 4381 260 ± 53 24 (12 - 48) 358 ± 69 4.3 ± 0.9 24 (12 - 24) 362 ± 71 4.4 ± 0.8 24 (12 - 48) 98.91 [94.87; 103.13] 97.01 [90.87; 103.57] 10.7 ± 4.1 0.9 ± 0.3 3 (2 - 8) 10.8 ± 4.1 0.8 ± 0.3 3 (2 - 10) 99.39 [86.37; 114.37] 109.20 [95.30; 125.11] 5 mg of Omnitrope 5 mg/1.5 mL solution for injection (N = 24) IGF-1 IGFBP-3 NEFA AUEC [h·µg/L] Emax [µg/L] tmax,E* [h] AUEC [h·mg/L] Emax [mg/L] tmax,E* [h] AUEC [h·mmol/L] Emax [mmol/L] tmax,E* [h] Ratio and 95% confidence interval [%] (N = 24) 101.50 [96.62; 106.62] 101.44 [95.78; 107.45] Results are presented as mean ± SD. *median value (min - max) for tmax OMNITROPE (somatropin for injection) Page 31 of 54 Table 13. Pharmacodynamic Parameters after a Single SC Administration of 5 mg Omnitrope Solution for Injection, of 5 mg Omnitrope 5 mg/mL Powder for Solution for Injection (5.8 mg/vial), and of 5 mg Genotropin® 5 mg/mL Powder for Solution for Injection – Study EP00-104 IGF-1 AUEC [h·µg/L] Emax [µg/L] tmax,E* [h] Ratio of LS-Means and 95% CI [%] 5 mg of 5 mg of 5 mg of Genotropin® Omnitrope Omnitrope 5.0 mg/1.5 mL powder for solution 5 mg/mL powder for solution for injection solution for injection for injection; 5.8 mg/vial (N = 35) (N = 35) (N = 35) 16712 ± 3847 16295 ± 3664 15960 ± 3557 218 ± 56 213 ± 49 209 ± 49 24 (12 - 48) 24 (12 - 48) 24 (12 - 48) X X AUEC: 102.35 [98.70 ; 106.13] Emax: 102.15 [94.28 ; 110.68] X X AUEC: 104.51 [100.78 ; 108.37] Emax:104.08 [99.34 ; 109.04] X X AUEC: 102.11 [98.47 ; 105.89] Emax: 102.19 [97.53 ; 107.06] Results are presented as mean ± SD. *median value (min - max) for tmax,E IGFBP-3 AUEC [h·mg/L] Emax [mg/L] tmax,E* [h] Ratio of LS-Means and 95% CI [%] 5 mg of 5 mg of 5 mg of Omnitrope Genotropin® Omnitrope 5.0 mg/1.5 mL 5 mg/mL powder for powder for solution solution for injection solution for injection for injection; 5.8 mg/vial (N = 35) (N = 35) (N = 35) 430 ± 61 427 ± 56 424 ± 57 4.9 ± 0.7 4.9 ± 0.6 4.9 ± 0.7 48 (24 - 96) 48 (12 - 96) 48 (16 - 72) X X AUEC: 100.49 [98.74 ; 102.27] Emax: 100.58 [97.90 ; 103.34] X X AUEC: 101.23 [99.47 ; 103.02] Emax: 101.12 [98.42 ; 103.89] X X AUEC: 100.73 [98.98 ; 102.52] Emax: 100.53 [97.85 ; 103.28] Results are presented as mean ± SD. *median value (min - max) for tmax,E OMNITROPE (somatropin for injection) Page 32 of 54 NEFA AUEC [h·mmol/L] Emax [mmol/L] tmax,E* [h] Ratio of LS-Means and 95% CI [%] 5 mg of 5 mg of 5 mg of Genotropin® Omnitrope Omnitrope 5 mg/mL powder for 5.0 mg/1.5 mL powder for solution for injection; solution for injection solution for injection 5.8 mg/vial (N = 35) (N = 35) (N = 35) 11.8 ± 3.8 11.5 ± 3.0 12.5 ± 3.8 1.0 ± 0.3 0.9 ± 0.3 1.0 ± 0.3 2 (0 - 16) 2 (1 - 24) 3 (1 - 16) X X AUEC: 101.96 [92.26 ; 112.67] Emax: 102.64 [94.65 ; 111.30] X X AUEC: 94.03 [85.09 ; 103.91] Emax:95.27 [87.85 ; 103.31] X X AUEC: 92.23 [83.46 ; 101.92] Emax: 92.92 [95.60 ; 100.65] Results are presented as mean ± SD. *median value (min - max) for tmax,E OMNITROPE (somatropin for injection) Page 33 of 54 Table 14. Pharmacodynamic Parameters after a Single SC Administration of 5 mg Omnitrope 10 mg/1.5 mL Solution for Injection, of 5 mg Omnitrope Powder for Solution for Injection (5.8 mg/vial), and of 5 mg Genotropin® 5 mg/mL Powder for Solution for Injection – Study EP00-105 IGF-1 AUEC [h·µg/L] Emax [µg/L] tmax,E* [h] Ratio of LS-Means and 95% CI [%] 5 mg of 5 mg of 5 mg of Genotropin® Omnitrope Omnitrope 10.0 mg/1.5 mL powder for solution 5 mg/mL powder for solution for injection solution for injection for injection; 5.8 mg/vial (N = 32) (N = 32) (N = 32) 20355 ± 5067 19829 ± 5107 19126 ± 5072 267 ± 64 265 ± 68 252 ± 67 24 (16 - 48) 24 (16 - 24) 24 (12 - 24) X X AUEC: 100.04 [93.47 ; 107.07] Emax: 100.42 [96.66 ; 104.32] X X AUEC: 108.71 [101.57 ; 116.36] Emax:105.90 [101.93 ; 110.02] X X AUEC: 108.67 [101.61 ; 116.22] Emax: 105.46 [101.55 ; 109.52] Results are presented as mean ± SD. *median value (min - max) for tmax,E IGFBP-3 AUEC [h·mg/L] Emax [mg/L] tmax,E* [h] Ratio of LS-Means and 95% CI [%] 5 mg of 5 mg of 5 mg of Omnitrope Genotropin® Omnitrope 10.0 mg/1.5 mL 5 mg/mL powder for powder for solution solution for injection solution for injection for injection; 5.8 mg/vial (N = 32) (N = 32) (N = 32) 471 ± 70 468 ± 67 459 ±66 5.4 ± 0.8 5.4 ± 0.8 5.3 ± 0.7 48 (16 - 96) 48 (0 - 72) 48 (24 - 72) X X AUEC: 98.21 [91.82 ; 105.04] Emax: 99.49 [96.67 ; 102.40] X X AUEC: 104.79 [97.97 ; 112.08] Emax: 102.14 [99.24 ; 105.12] X X AUEC: 106.70 [99.83 ; 114.04] Emax: 102.66 [99.78 ; 105.62] Results are presented as mean ± SD. *median value (min - max) for tmax,E OMNITROPE (somatropin for injection) Page 34 of 54 NEFA AUEC [h·mmol/L] Emax [mmol/L] tmax,E* [h] Ratio of LS-Means and 95% CI [%] 5 mg of 5 mg of 5 mg of Genotropin® Omnitrope Omnitrope 5 mg/mL powder for 10.0 mg/1.5 mL powder for solution for injection; solution for injection solution for injection 5.8 mg/vial (N = 32) (N = 32) (N = 32) 13.1 ± 3.8 12.8 ± 3.7 12.0 ± 4.2 1.1 ± 0.3 1.1 ± 0.3 1.0 ± 0.3 3 (1 - 16) 3 (2 - 16) 3 (1 - 20) X X AUEC: 103.25 [94.53 ; 112.78] Emax: 96.87 [88.35 ; 106.21] X X AUEC: 113.01 [103.56 ; 123.33] Emax:111.81 [102.07 ; 122.48] X X AUEC: 109.46 [100.30 ; 119.45] Emax: 115.43 [105.37 ; 126.44] Results are presented as mean ± SD. *median value (min - max) for tmax,E Conclusion: The pharmacodynamic responses in terms of IGF-1, IGFBP-3, and NEFA were highly comparable after single doses of 5 mg of the different strengths and formulations of Omnitrope and of Genotropin®. OMNITROPE (somatropin for injection) Page 35 of 54 CLINICAL EFFICACY AND SAFETY STUDIES Pediatric Growth Hormone Deficiency (GHD) Five Phase III studies were performed in a total of 190 pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone (See Table 15). Table 15: Study Demographics and Trial Design for Phase III Trials Study Number Length of Study EP2K-99-PhIII 6 months EP2K-00-PhIIIFo 3 months EP2K-00-PhIIIAQ Part A 6 months -from months 9 to 15 of overall GH therapy Trial Design Dosage, Route of Administration and Duration Study Subjects (N) Phase III, randomized, open, multicentre, controlled, parallel two-group study of Omnitrope lyophilizate and ® Genotropin in GHD children with growth failure S: Omnitrope powder for solution for injection; 5.8 mg/vial 89 Phase III, open, multicentre, comparative, parallel twogroup study of Omnitrope lyophilizate and Omnitrope liquid. ® 86 EP2K-00-PhIIIb-E EP2K-02-PhIII-Lyo 15 months, ongoing from months 15 - 30 of overall GH therapy) 30 months, ongoing 24 months, ongoing Phase III, open, multicentre, non-comparative follow-up study of Omnitrope liquid. Phase III, open, multicentre study to demonstrate the efficacy and safety of Omnitrope liquid 5.0 mg/1.5 mL in the treatment of growth-deficient children due to GHD. Phase III, open, multicentre study to demonstrate the efficacy and safety of Omnitrope lyophilizate 5.8 mg in the treatment of growth-deficient children due to GHD. S1: 27M, 15F 8.8 yrs (4-14 yrs) S2: 20M, 24F 8.1 yrs (3-14 yrs) S2: Omnitrope 5mg/1,5mL solution for injection EP2K-00-PhIIIAQ Part B S: 28M, 16F 7.8 yrs (3-13 yrs) C: 21M/24F 7.4 yrs (2-14 yrs) C: Genotropin 5mg/mL powder 0.03 mg/kg SC, once daily S1: Omnitrope powder for solution for injection; 5.8 mg/vial Gender, Mean Age (Range) 0.03 mg/kg SC, once daily Omnitrope 5mg/1,5mL solution for injection 86 47M, 39F 8.9 yrs (3-15 yrs) 0.03 mg/kg SC, once daily Omnitrope 5mg/1,5mL solution for injection 50 29M, 21F 9.0 yrs (5-12 yrs) 0.03 mg/kg SC, once daily Omnitrope powder for solution for injection; 5.8 mg/vial 51 30M, 21F 8.0 yrs (2.5-14.2 yrs) 0.03 mg/kg SC, once daily C: Comparator S: Omnitrope lyophilize powder with active ingredient from Covance Biotechnology, USA (not available on the market). S1: Omnitrope lyophilize powder with active ingredient from Sandoz, Austria. S2: Omnitrope solution for injection with active ingredient from Sandoz, Austria. OMNITROPE (somatropin for injection) Page 36 of 54 The efficacy and safety of Omnitrope was compared with Genotropin®, a somatropin product authorized for treatment of growth hormone deficiency (GHD) in pediatric patients. In a randomized clinical trial involving a total of 89 GHD children, 44 patients received Omnitrope powder for solution for injection (5.8 mg/Vial) and 45 patients received Genotropin® for 9 months. In both groups, somatropin was administered as a daily subcutaneous injection at a dose of 0.03 mg/kg. Subsequently, after 9 months of treatment, patients who had received Genotropin® switched to Omnitrope Solution (5.0 mg/mL). Omnitrope Powder was continued beyond 9 months on the same treatment and dose. After 15 months of treatment, all patients were switched to Omnitrope Solution (5.0 mg/mL) to collect long-term efficacy and safety data for Omnitrope Solution. The route of administration, dose and duration was the same for Omnitrope Powder and Omnitrope Solution. Figure 1 Design of the three consecutive Phase III studies EP2K-99-PhIII/ EP2K-00-PhIIIFo/EP2K-00-PhIIIAQ EP2K-00-PhIIIFo EP2K-00-PhIIIAQ EP2K-99-PhIII Part A 0 3 6 9 12 Part B 15 •Omnitrope lyophilizate •Omnitrope (N=44) lyoph. (N=42) •Omnitrope •Genotropin® (N=45) liquid (N=44) Drug Product: Drug Product: Omnitrope Lyophilized Powder (API Covance Biotechnology, USA ) (5.8mg/vial) Omnitrope Lyophilized Powder (API Sandoz GmbH, Kundl, Austria): 5.8mg/vial) ® Genotropin Lyophilized 5 mg/mL powder 18 24 30 Omnitrope liquid (N=86) Omnitrope Liquid (API, Sandoz GmbH, Kundl, Austria) 5.0 mg/1.5 mL 0.03 mg/kg/day, subcutaneous injection, once daily The efficacy results of treatment with Omnitrope lyophilized powder, Omnitrope Solution and the Genotropin® are summarized in Table 16, Table 17 and Table 18. OMNITROPE (somatropin for injection) Page 37 of 54 Table 16: Key primary endpoints in Phase III Studies EP2K-99-PhIII/EP2K-00-PhIIIFo (mean ± SD) ® Omnitrope lyophilizate N=44 Mean (SD) Genotropin N=45 Mean (SD) Height Velocity (cm/yr) Pre-treatment Month 9 Change from pretreatment to Month 9 3.8 (1.2) 10.7 (2.6) 6.9 (3.1) 3.9 (0.8) 10.7 (2.9) 6.8 (3.2) Height velocity SDS Pre-treatment Month 9 Change from pretreatment to Month 9 -2.3 (1.3) 5.9 (3.4) 8.2 (4.0) -2.3 (0.9) 5.0 (2.9) 7.4 (3.2) Height SDS Pre-treatment Month 9 Change from pretreatment to Month 9 -3.0 (0.7) -2.3 (0.7) 0.8 (0.4) -3.1 (0.9) -2.5 (0.7) 0.7 (0.5) IGF-1 Pre-treatment Month 9 158.6 (92.0) 291.1 (174.0) 157.7 (43.0) 301.9 (182.9) IGFBP-3 Pre-treatment Month 9 3.5 (1.3) 4.6 (3.0) 3.5 (1.0) 4.0 (1.5) Treatment effect Mean (95% CI) -0.1 (-1.5;1.3) -0.9 (-2.4;0.7) -0.1 (-0.3;0.1) Table 17: Key primary endpoints in Phase III Study EP2K-00-PhIIIAQ Part A (mean ± SD) Omnitrope lyophilizate N=42 Mean (SD) Omnitrope liquid N=44 Mean (SD) Height Velocity (cm/yr) Month 9 Month 15 Change from Month 9 to Month 15 10.7 (2.6) 9.3 (1.7) -1.4 (1.4) 10.7 (2.9) 9.4 (2.2) -1.4 (1.3) Height velocity SDS Month 9 Month 15 Change from Month 9 to Month 15 5.9 (3.4) 4.4 (2.9 -1.5 (1.7) 5.0 (2.9) 3.6 (2.2) -1.4 (1.4) Height SDS Month 9 Month 15 Change from Month 9 to Month 15 -2.3 (0.7) -2.0 (0.7) 0.3 (0.2) -2.5 (0.7) -2.2 (0.7) 0.3 (0.2) OMNITROPE (somatropin for injection) Treatment effect Mean (95% CI) 0.0 (-0.6;0.6) 0.1 (-0.6;0.7) 0.0 (-0.1;0.1) Page 38 of 54 IGF-1 Month 9 Month 15 291 (174) 300 (225) 302 (183) 323 (189) IGFBP-3 Month 9 Month 15 4.6 (3.0) 4.6 (1.3) 4.0 (1.5) 4.9 (1.4) Table 18: Key primary endpoints in Phase III Study EP2K-00-PhIIIAQ Part B (mean ± SD) Omnitrope liquid N=86 Mean (SD) Height Velocity (cm/yr) Month 15 Month 30 9.3 (2.0) 7.3 (1.7) Height velocity SDS Month 15 Month 30 4.0 (2.6) 1.8 (2.2) Height SDS Month 15 Month 30 -2.1 (0.7) -1.7 (0.9) IGF-1 Month 9 Month 15 296.7 (177.5) 311.8 (206.3) IGFBP-3 Month 9 Month 15 4.3 (2.4) 4.8 (1.4) The three sequential Phase III studies EP2K-99-PhIII, EP2K-00-PhIIIFo, and EP2K-00-PhIIIAQ in the same group of patients have demonstrated the following: • • Omnitrope has a clinical efficacy and safety profile in the treatment of GHD children which is comparable to Genotropin®. The lyophilized powder and liquid formulations of Omnitrope have comparable clinical efficacy and safety profiles in the treatment of children with GHD. Results from studies EP2K-02-PhIII-Lyo and EP2K-00-PhIIIb-E Two additional open-label Phase III studies, EP2K-02-PhIII-Lyo and EP2K-00-PhIIIb-E, were initiated to further investigate the efficacy and safety of Omnitrope lyophilized powder for solution for injection (5.8 mg/vial) and Omnitrope Solution (5.0 mg/1.5 mL solution for injection), respectively, in somatropin treatment-naïve prepubertal children with growth hormone deficiency and to confirm the low immunogenicity of both products. Interim analyses of the EP2K-02-PhIII-Lyo and EP2K-00-PhIIIb-E studies at 24 and 30 months of GH treatment, respectively, were performed to provide efficacy and safety data. OMNITROPE (somatropin for injection) Page 39 of 54 Growth of the children treated with Omnitrope liquid and Omnitrope powder was comparable. The small differences in growth parameters between the studies can be explained by the average higher age of the children in study EP2K-00-PhIIIb-E. The efficacy results were consistent with the results obtained in previous studies with Omnitrope and as expected with regard to the results obtained with other rhGH products in the treatment of GHD children. With regard to secondary efficacy results, synthesis of IGF-1 and the corresponding binding protein IGFBP-3 was directly stimulated by Omnitrope. The safety profile of Omnitrope is consistent with the profile for rhGH treatment of previously untreated GHD children and confirmed the low immunogenicity of Omnitrope. In summary, safety and efficacy of rhGH treatment with Omnitrope liquid and Omnitrope powder were confirmed. Table 19: Baseline Growth Characteristics and Effect of OMNITROPETM in Phase III Studies (mean ± SD) EP2K-02-PhIII-Lyo Omnitrope powder for solution for injection; 5.8 mg/vial N=51 Mean (SD) EP2K-00-PhIIIb-E Omnitrope 5.0 mg/1.5 mL solution for injection N=50 Mean (SD) Height Velocity (cm/yr) Month 0 Month 12 Month 24 Month 30 3.72 (1.40) 10.39 (2.50) 7.58 (1.63) 3.8 (1.17) 9.3 (2.09 8.2 (1.46 8.8 (1.72) Height velocity SDS Month 0 Month 12 Month 24 Month 30 -2.25 (1.68) 5.22 (2.96) 2.09 (2.25) -2.20 (1.34) 4.12 (2.90) 2.07 (2.09) 2.65 (0.85) Height SDS Month 0 Month 12 Month 24 Month 30 -2.97 (0.87) -2.15 (0.74) -1.76 (0.75) -3.05 (0.59) -2.29 (0.56) -1.97 (0.61) -1.80 (0.47) IGF-1 Month 0 Month 12 Month 24 Month 30 78.8 (46.9) 208.4 (105.9) 208.8 (92.7) 128 (58) 245 (115) 293 (108) 296 (136) IGFBP-3 Month 0 Month 12 Month 24 Month 30 2.73 (1.03) 3.65 (0.85) 3.89 (0.86) 2.95 (0.66) 4.15 (0.89) 3.76 (0.69) OMNITROPE (somatropin for injection) 3.26 (1.17) Page 40 of 54 Adult Growth Hormone Deficiency (GHD) There are no clinical trials conducted with Omnitrope in adult GHD patients. The use of Omnitrope in adult GHD patients is supported in consideration of the similar product quality characteristics of Omnitrope and Genotropin® and the similar pathophysiology of adult GHD to GHD in children. In addition, comparative non-clinical, human pharmacokinetic/pharmacodynamic, and clinical efficacy and safety studies in children (see the above) have been conducted to demonstrate comparable clinical profiles between Omnitrope and the reference product. DETAILED PHARMACOLOGY ANIMAL PHARMACOLOGY Pharmacodynamics The efficacy of recombinant human growth hormone has been measured by different methods, mostly in the rat. Growth hormone is an anabolic hormone, and exerts a wide spectrum of actions in vivo and in vitro. Some of these important effects are as follows: stimulation of postnatal somatic growth; insulin-like effects; lipolytic. The pharmacodynamic properties of Omnitrope were evaluated in rat weight gain bioassays and a rat tibial width assay. Rat Weight Gain Bioassay When a growing rat is hypophysectomized, it stops gaining weight and growing in length. Since somatropin promotes growth of skeletal and soft tissue and influences the metabolism of carbohydrate, fat, and protein, it leads to weight gain in the rats. The rat weight gain bioassays were performed to compare the efficacy of different formulations of human growth hormone to that of international standards when administered to hypophysectomized male Wistar rats. Groups of 10 male rats were given Omnitrope drug substances, Omnitrope drug products, reference somatropin, vehicle or an international standard at 5 or 10 mcg/animal daily, for 10 consecutive days by subcutaneous injections. The results from the comparative biological assays showed the comparability of different batches of Omnitrope drug substances and Omnitrope drug products, the marketed reference somatropin and two international reference standards of human somatropin regarding their specific action on body weight gain. The results confirm that Omnitrope is an authentic human growth hormone with the same quantitative activity as international standards and the marketed reference somatropin. Rat Tibial Width Assay The rat tibial width assay was performed to compare the potency of different human growth hormone products, each with a high and low content of product-related substances, by determining their effect on the increase of the width of the proximal epiphysis of the tibia in immature hypophysectomized rats with that of a standard preparation. The different formulations of human GH were administered by daily subcutaneous injections to rats for 10 consecutive days. OMNITROPE (somatropin for injection) Page 41 of 54 Groups of 8 male rats were given Omnitrope liquid 5.0 mg/1.5 mL and Omnitrope lyophilizate 5.8 mg, marketed reference somatropins, vehicle or the standard at 6.7 or 53.3 mcg/animal/day. The pharmacodynamic effects on the increase of the width of proximal epiphysis of the tibia in immature hypophysectomized rats were comparable for the different human growth hormone products tested (Omnitrope, marketed recombinant preparations, each with a high and low content of product-related substances) and were similar to the potency of the international standard of human somatropin. TOXICOLOGY In studies with Omnitrope regarding subacute toxicity and local tolerance, no clinically relevant effects have been observed. In other studies with somatropin regarding general toxicity, local tolerance and reproduction toxicity, no clinically relevant effects have been observed. With somatropins, in vitro and in vivo genotoxicity studies on gene mutations and induction of chromosome aberrations have been negative. An increased chromosome fragility has been observed in one in vitro study on lymphocytes taken from patients after long term treatment with somatropin and following the addition of the radiomimetic drug bleomycin. The clinical significance of this finding is unclear. In another study with somatropin, no increase in chromosomal abnormalities was found in the lymphocytes of patients who had received long-term somatropin therapy. REPEAT DOSE TOXICITY 14 Day SC Toxicity Test in the Rat Groups of 10 male and 10 female Sprague-Dawley rats were given Omnitrope bulk solution at 0, 2 or 8 mg/kg/day SC for 14 days in a full conventional subacute toxicity test, including pharmacokinetic analyses on days 1, 7 and 14. There were no abnormal clinical signs during the study and no relevant adverse reactions were seen at the injection sites. Treated females showed a dose-related increase in weight gain, accompanied by increased food consumption, but weight gain and food consumption of males were the same as that of the controls. Also, abnormal hematological results were not found. Clinical chemistry tests in males were normal. In females there were decreases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and an increase in alkaline phosphatase (ALP), as well as a decrease in serum albumin. The changes in ALT and AST were small, although significant. The increase in ALP is very likely due to increased growth activity. The change in albumin level is insignificant. Small changes are also described in triglyceride OMNITROPE (somatropin for injection) Page 42 of 54 levels that are likely due to the metabolic effects of treatment. There were small increases in relative heart and kidney weight in females but no effect on organ weight in males. Also, histopathological abnormalities were not observed. Omnitrope had no toxic effect and the changes observed in the female animals likely represented its specific pharmacodynamic action. Subchronic Toxicity Similar conclusions were reached in studies comparing the subchronic toxicity of biosynthetic human growth hormone in rats and monkeys. In these studies, somatropin was injected subcutaneously in 120 Wistar rats (60 males, 60 females) for 90 days and in cynomolgus monkeys for 30 days. The daily doses were 0.16, 1.1, 3.3 mg/kg, respectively in rats and 0.05 and 5 mg/kg, respectively in monkeys. Somatropin was well tolerated in both rats and monkeys. No drug related deaths occurred and all animals appeared to be normal and also behaved normally throughout the dosing period. Increased body weight gain, increased food consumption and increased organ weights were seen in rats in the high and intermediate dose groups. The treatment related findings may be explained as direct or secondary manifestations of exaggerated pharmacological effects of growth hormone. Toxicokinetics As part of the 14-day repeat-dose toxicity study in rats, serum was collected from selected animals in all groups on days 1, 7 and 14 at 0, 2, 4, 6 and 10 hours postdosing. The hGH concentration was measured by an immunoradiometric assay using an anti-human somatropin antibody. There was slight accumulation of GH over the 14 days of treatment indicated by small increases in the predosing levels on days 7 and 14 in the high-dose group. Furthermore, the circulating level of hGH had not returned to baseline (0) 10 hours postdosing on day 14 in the 2 mg/kg group and on days 1, 7 and 14 in the 8 mg/kg animals. As the dose of hGH was increased there was a subproportional increase in Cmax and AUC, resulting in apparently similar drug exposure in the 2 dosage groups. Release from the injection sites appeared slower on day 14 than day 1. Total body exposure to Omnitrope appeared lower on day 14 than on day 1. In fact, the relatively small numbers of sampled animals resulted in some uncertainty about the values cited. LOCAL TOLERANCE Two local tolerance studies were performed in rabbits. In the first study, two formulations of Omnitrope (liquid and lyophilized powder), as well as their vehicles, were administered daily for 7 days to groups of 4 male and 4 female rabbits by intramuscular (IM), intravenous (IV) or subcutaneous (SC) injections at a dose of 5 mg/animal. There were signs of mechanical injection trauma in all groups. OMNITROPE (somatropin for injection) Page 43 of 54 Omnitrope liquid and its vehicle were associated with slight erythema at the sites of the IV injections and some local induration. The SC injection sites in all groups showed small hemorrhages attributed to mechanical trauma and minimal edema and erythema, slightly more marked after the administration of Omnitrope lyophilizate, and some induration after the administration of the vehicle of that formulation. The results showed that both formulations had a slight local effect after IV or SC administrations, but not after repeated IM injection. The intensity of the local reactions observed did not suggest severe local intolerance to either formulation. In the second study, Omnitrope liquid 10.0 mg/1.5 ml (low and high content of product-related substances), Omnitrope lyophilized powder 5.8 mg, Genotropin® 5 mg and 0.9% saline were administered by a single injection to groups of 6 males by IM, IV, intra-arterial (IA), perivenous (PV) or SC injections at a dose of 5 mg/animal. Following the administration of Omnitrope liquid 10.0 mg/1.5 mL (low and high content of product-related substances), Omnitrope lyophilized powder 5.8 mg and Genotropin® 5 mg, macroscopic changes were not observed at the injection sites over the period of study in any of the animals. Furthermore, histopathological examination showed that all the formulations tested were tolerated as well as the saline control. OMNITROPE (somatropin for injection) Page 44 of 54 REFERENCES 1. Jorgensen JOL. Human growth hormone replacement therapy; Pharmacological and clinical aspects. Endoc Reviews 12: 189-207, 1991. 2. Product Monograph, Genotropin®, Pfizer Canada Inc., Kirkland, Quebec, Control No.: 087297, Date of Approval: November 4th, 2003. 3. Romer T, Peter F, Saenger P, Starzyk J, Koehler B, Korman E, Walczak M: Efficacy and safety of a new ready-to-use recombinant human growth hormone solution. J.Endocrinol.Invest. 2007;30:578-589. OMNITROPE (somatropin for injection) Page 45 of 54 IMPORTANT: PLEASE READ PART III: CONSUMER INFORMATION (Lyophilized Powder) Pr OMNITROPE™ (Somatropin for Injection) Lyophilized powder: 5.8 mg/vial This leaflet is part III of a three-part "Product Monograph" published when Omnitrope was approved for sale in Canada and is designed specifically for consumers. This leaflet is a summary and will not tell you everything about Omnitrope. Contact your doctor or pharmacist if you have any questions about the drug. ABOUT THIS MEDICATION What the medication is used for: Children: • Omnitrope is indicated for long-term treatment of children with growth failure due to an inadequate secretion of growth hormone. Other causes of short stature should be excluded. Adults: • Omnitrope is indicated for long-term replacement therapy in adults with growth hormone deficiency due to underlying hypothalamic or pituitary disease or who were growth deficient during childhood. Growth hormone deficiency should be confirmed by an appropriate growth hormone stimulation test. Patients who were diagnosed as growth hormone deficient during childhood must be retested before treatment starts. What it does: Omnitrope is used to increase growth hormone levels in children and adults unable to produce adequate amounts naturally. Omnitrope may produce bone growth in children where the ends of the long bones have not yet hardened. In both adults and children requiring growth hormone replacement, Omnitrope helps in the development of muscles and causes fat to be used for energy. In adults with growth hormone deficiency, Omnitrope plays an important role in maintaining an improved ratio of body fat to lean mass. When it should not be used: • If you or your child have acute critical illness due to complications following open-heart or abdominal surgery, multiple accidental trauma, or acute respiratory failure. • If your child’s growth areas of the bones have closed • In patients with any evidence of an active cancer (intracranial lesion). • In patients with Prader-Willi syndrome who are very overweight or have severe breathing problems. • If you or your child are allergic to benzyl alcohol. • In patients who are hypersensitive to somatropin or to any ingredient in the formulation OMNITROPE (somatropin for injection) Omnitrope treatment is not recommended during pregnancy and lactation. Omnitrope is not recommended for use in patients who have undergone renal transplant. What the medicinal ingredient is: Somatropin (recombinant human growth hormone) What the important non - medicinal ingredients are: Omnitrope Lyophilized Powder: Glycine, disodium hydrogen phosphate, sodium dihydrogen phosphate. Diluent Cartridge: Bacteriostatic Water for Injection USP (benzyl alcohol preserved) What dosage forms it comes in: Omnitrope (somatropin for injection) is supplied as follows: Lyophilized powder: 5.8 mg/vial WARNINGS AND PRECAUTIONS Serious Warnings and Precautions • • There have been reports of fatalities associated with the use of growth hormone in pediatric patients with Prader-Willi syndrome who have one or more of the following risk factors: severe obesity, history of respiratory impairment or sleep apnea or unidentified respiratory infection ( See WARNINGS AND PRECAUTIONS - CONGENITAL DISORDERS). Patients with acute critical illness suffering complications following open-heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure or similar conditions should not be treated with somatropin (See WARNINGS AND PRECAUTIONS - PERIOPERATIVE CONSIDERATIONS). Omnitrope therapy should be carried out under the regular guidance of a doctor who is experienced in the diagnosis and management of patients with growth hormone deficiency. BEFORE you use Omnitrope talk to your doctor or pharmacist: For all patients • If you or your child have breathing problems, sleep apnea or snoring. • If you or your child are experiencing headaches, nausea, visual changes and/or vomiting. You or your child may have a condition called Intracranial Hypertension (IH). • If you or your child have a history of an intracranial lesion. Page 46 of 54 • • • If you or your child have diabetes. Omnitrope may affect your body’s or your child’s body’s response to insulin. The insulin dose may require adjustment. If you or your child have hypothyroidism. Omnitrope may reduce the levels of thyroid hormone. If you or your child are allergic to benzyl alcohol. Omnitrope 5.8 mg/vial Lyophilized Powder requires reconstitution with a diluent that contains benzyl alcohol. For pediatric patients • If your child has a history of scoliosis (a condition which affects the spine). Because growth hormone increases growth rate, patients with a history of scoliosis who are treated with Omnitrope should be monitored for progression of scoliosis. Missed Dose: Missing injections can interfere with the effectiveness of the medication. Talk to your doctor if this should happen. Do not try to make up for missed injections by “doubling up” on injections. Note: Do not reconstitute Omnitrope or inject it, until you have been taught the proper technique by your healthcare provider and you understand the instructions. Ask your healthcare provider or pharmacist if you have any questions about injecting OMNITROPE. INSTRUCTIONS FOR OMNITROPE 5.8 MG/VIAL • For adult patients If you are pregnant or nursing. The dosage of Omnitrope must be adjusted for the individual patient. The weekly dose should be divided into daily subcutaneous injections (administered preferably in the evening). Omnitrope may be given in the thigh, buttocks, or abdomen; the site of SC injections should be rotated daily to help prevent lipoatrophy. Experience with prolonged growth hormone treatment in adults is limited. The following instructions explain how to inject Omnitrope 5.8 mg/vial: INTERACTIONS WITH THIS MEDICATION Glucocorticoids (steroids) may decrease the effects of Omnitrope. If you or your child are receiving concomitant glucocorticoid (steroid) therapy contact your doctor. Steroid doses may need to be adjusted. Omnitrope may affect your or your child’s body’s response to insulin. Contact your doctor if you/your child have diabetes. It may be necessary to adjust the dosage of diabetes medications. You should tell the doctor or nurse about all medicines that you/your child are taking, even those obtained without a doctor’s prescription. Do not inject Omnitrope yourself until you have been taught the proper technique by your healthcare provider and you understand the instructions. • Omnitrope 5.8 mg/vial is for multiple use. • The concentration of Omnitrope after reconstitution is 5.0 mg/mL. • After reconstitution, Omnitrope solution contains a preservative and should not be used in newborns. • Omnitrope solution is for subcutaneous injection. • The injection sites should be rotated daily to help prevent lipoatrophy. Preparation Collect necessary items before you begin: PROPER USE OF THIS MEDICATION Usual Dose: Your doctor will calculate the dose of Omnitrope based on you/your child’s body weight. Your doctor will instruct you on what is the best dosage of Omnitrope for you based on your individual needs. Use Omnitrope exactly as your doctor tells you to. Overdosage: Call your doctor immediately if you or your child take more than the amount of Omnitrope prescribed by your doctor. • • • • • OMNITROPE (somatropin for injection) a vial with 5.8 mg Omnitrope powder for solution for injection. a cartridge with diluent (Bacteriostatic Water for Injection containing benzyl alcohol as preservative). a transfer set for mixing and transferring the reconstituted solution back into the cartridge. the Omnitrope Pen L, an injection device specifically developed for use with Omnitrope 5.0 mg/mL reconstituted solution for injection (not supplied in the pack; see Instructions for Use of the transfer set and of the injection device). 2 alcohol swabs (not supplied in the pack). Page 47 of 54 Wash your hands before you start with the next steps. Reconstituting Omnitrope 5.8 mg/vial • Remove the protective cap from the vial. With one alcohol swab, disinfect both the rubber membrane of the vial with powder and the cartridge containing diluent. • • • • Use the transfer set to transfer all of the diluent from the cartridge into the vial. Follow the directions that come with the transfer set. Gently swirl the reconstituted vial until the content is completely dissolved. Do not shake. If the solution is cloudy or contains particles, it should not be used. The solution must be clear and colourless after mixing. Transfer all of the dissolved solution back into the cartridge using the transfer set. Injecting Omnitrope 5.8 mg/vial Put the cartridge with the Omnitrope solution into the Pen L for injection. Follow the Instructions for Use of the Pen Injector. • Eliminate any air bubbles. • Select the site of injection. The best sites of injection are tissues with a layer of fat between skin and muscle, such as the thigh, buttocks, or abdomen as in the pictures shown below. Do not inject near your belly button (navel) or waistline. • • Insert the needle into the skin the way your doctor has taught you. • With one hand, pinch a fold of loose skin at the injection site. With your other hand, hold the Pen L as you would a pencil. Insert the needle into the pinched skin straight in or at a slight angle (an angle of 45° to 90°). • Pull the needle straight out of the skin. After injection, press the injection site with a small bandage or sterile gauze if needed for bleeding, for several seconds. Do not massage or rub the injection site. After Injecting Omnitrope 5.8 mg/vial After injection, press the injection site with a small bandage or sterile gauze for several seconds. Do not massage the injection site. • Remove the needle from the pen using the outer needle cap and discard the needle. This will keep Omnitrope sterile and prevent leaking. It will also stop air from going back into the pen and the needle clogging up. Do not share your needles. Do not share your pen. • Leave the cartridge in the pen, replace the pen cap and store in a refrigerator (at 2-8°C) and discard any unused solution 28 days after reconstitution. • The solution should be clear after removal from the refrigerator. Do not use if the solution is cloudy or contains particles. • Do not inject Omnitrope yourself until you have been taught the proper technique by your healthcare provider and you understand the instructions. SIDE EFFECTS AND WHAT TO DO ABOUT THEM • • Make sure you rotate the injection sites on your body. Inject at least 1 cm from your last injection site and change the places on your body where you inject, as you have been taught. Before you make an injection, clean your skin well with an alcohol swab. Wait for the area to air dry. OMNITROPE (somatropin for injection) Like all medicines, Omnitrope can cause side effects, although not everybody experiences them. Please ask your doctor for advice when you experience any of the symptoms described below. Page 48 of 54 SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM Symptom/effect Talk with your doctor or pharmacist Only if severe Common General disorders and reactions at the injection site. In children: transient local skin reactions. Musculoskeletal system, connective tissues, bones. In adults: stiffness of the limbs, joints and muscle pain. Nervous System. In adults: sensory disturbances. Metabolic and nutritional disturbances. In adults: mild edema. In all cases 9 9 9 9 Disorders of the immune system such as development of antibodies. 9 Uncommon Musculoskeletal system, connective tissues, bones. In children: stiffness of the limbs, joints and muscle pain. 9 Rare Nervous System -In children: sensory disturbances -In adults: carpal tunnel syndrome Metabolic and nutritional disturbances, in children: mild edema. Nervous System such as: benign intracranial hypertension. Metabolic and nutritional disturbances such as: Diabetes mellitus. Very Rare Leukemia – Benign and malignant neoplasms. Stop taking drug and call your doctor or pharmacist REPORTING SUSPECTED SIDE EFFECTS To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance: By toll-free telephone: 1 866-234-2345 By toll-free fax: 1 866-678-6789 Online: www.healthcanada.gc.ca/medeffect By email: [email protected] By regular mail: Canada Vigilance National Office Marketed Health Products Safety and Effectiveness Information Bureau Marketed Health Products Directorate Health Products and Food Branch Health Canada Tunney’s Pasture, AL 0701C Ottawa ON K1A 0K9 NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice. MORE INFORMATION 9 9 9 9 9 This is not a complete list of side effects. For any unexpected effects while taking Omnitrope, contact your doctor or pharmacist. This document, plus the full Product Monograph prepared for health professionals, can be obtained by contacting the sponsor, Sandoz Canada Inc., at: 1-800-361-3062 or by written request at: 145, Jules-Léger Boucherville, (QC), Canada J4B 7K8 or by e-mail at : [email protected] This leaflet was prepared by Sandoz Canada Inc. Last revised: April 2009 HOW TO STORE IT • Omnitrope must be refrigerated between 2 - 8°C, both in powder form and after reconstitution. • Discard any unused solution 28 days after reconstitution. • Do NOT freeze. • Omnitrope is light sensitive and should be stored in the original package. • Do NOT use after the expiry date on the label and carton. • Do NOT use Omnitrope if the solution is cloudy or contains particles. • Keep out of reach of children. OMNITROPE (somatropin for injection) Page 49 of 54 PART III: CONSUMER INFORMATION (Solution for Injection) Pr OMNITROPE™ (Somatropin for Injection) Solution for Injection: 5.0 mg/1.5 mL and 10 mg/1.5 mL This leaflet is part III of a three-part "Product Monograph" published when Omnitrope was approved for sale in Canada and is designed specifically for consumers. This leaflet is a summary and will not tell you everything about Omnitrope. Contact your doctor or pharmacist if you have any questions about the drug. ABOUT THIS MEDICATION What the medication is used for: Children: • Omnitrope is indicated for long-term treatment of children with growth failure due to an inadequate secretion of growth hormone. Other causes of short stature should be excluded. Adults: • Omnitrope is indicated for long-term replacement therapy in adults with growth hormone deficiency due to underlying hypothalamic or pituitary disease or who were growth deficient during childhood. Growth hormone deficiency should be confirmed by an appropriate growth hormone stimulation test. Patients who were diagnosed as growth hormone deficient during childhood must be retested before treatment starts. What it does: Omnitrope is used to increase growth hormone levels in children and adults unable to produce adequate amounts naturally. Omnitrope may produce bone growth in children where the ends of the long bones have not yet hardened. In both adults and children requiring growth hormone replacement, Omnitrope helps in the development of muscles and causes fat to be used for energy. In adults with growth hormone deficiency, Omnitrope plays an important role in maintaining an improved ratio of body fat to lean mass. When it should not be used: • If you or your child have acute critical illness due to complications following open-heart or abdominal surgery, multiple accidental trauma, or acute respiratory failure. • If your child’s growth areas of the bones have closed • In patients with any evidence of an active cancer (intracranial lesion). • In patients with Prader-Willi syndrome who are very overweight or have severe breathing problems. • If you or your child are allergic to benzyl alcohol. • In patients who are hypersensitive to somatropin or to any ingredient in the formulation. OMNITROPE (somatropin for injection) Omnitrope treatment is not recommended for use during pregnancy and lactation. Omnitrope is not recommended for use in patients who have undergone renal transplant. What the medicinal ingredient is: Somatropin (recombinant human growth hormone) What the important non - medicinal ingredients are: 5.0 mg/1.5 mL cartridge contains: disodium hydrogen phosphate heptahydrate, sodium dihydrogen phosphate dihydrate, mannitol, poloxamer 188, benzyl alcohol, water for injection. 10.0 mg/1.5 mL cartridge contains: disodium hydrogen phosphate heptahydrate, sodium dihydrogen phosphate dihydrate, glycine, poloxamer 188, phenol, water for injection. What dosage forms it comes in: Omnitrope (somatropin for injection) is supplied as a solution: 5.0 mg/1.5 mL cartridge and 10 mg/1.5 mL cartridge. WARNINGS AND PRECAUTIONS Serious Warnings and Precautions • • There have been reports of fatalities associated with the use of growth hormone in pediatric patients with Prader-Willi syndrome who have one or more of the following risk factors: severe obesity, history of respiratory impairment or sleep apnea or unidentified respiratory infection (See WARNINGS AND PRECAUTIONS - CONGENITAL DISORDERS). Patients with acute critical illness suffering complications following open-heart surgery, abdominal surgery, multiple accidental trauma, acute respiratory failure or similar conditions should not be treated with somatropin (See WARNINGS AND PRECAUTIONS - PERIOPERATIVE CONSIDERATIONS). Omnitrope therapy should be carried out under the regular guidance of a doctor who is experienced in the diagnosis and management of patients with growth hormone deficiency. BEFORE you use Omnitrope talk to your doctor or pharmacist if: For all patients • If you or your child have breathing problems, sleep apnea or snoring. • If you or your child are experiencing headache, nausea, visual changes and/or vomiting. You or your child may have a condition called intracranial hypertension. • If you or your child have a history of an intracranial lesion. • If you or your child have diabetes. Omnitrope may affect your or your child’s body’s response to insulin. The insulin dose may require adjustment. Page 50 of 54 • • If you or your child have hypothyroidism. Omnitrope may reduce the levels of thyroid hormone. If you or your child are allergic to benzyl alcohol. Omnitrope Lyophilized Powder requires reconstitution with a diluent that contains benzyl alcohol. For pediatric patients. • If your child has a history of scoliosis (a condition which affects the spine). Because growth hormone increases growth rate, patients with a history of scoliosis who are treated with Omnitrope should be monitored for progression of scoliosis. For adult patients If you are pregnant or nursing. • Experience with prolonged growth hormone treatment in adults is limited. INSTRUCTIONS FOR USE OMNITROPE 5.0 mg/1.5mL (somatropin for injection) How to inject Omnitrope 5.0 mg/1.5 mL The following instructions explain how to inject Omnitrope 5.0 mg/1.5 mL yourself. Please read the instructions carefully and follow them step by step. Your doctor or other suitably qualified healthcare professionals will show you how to inject Omnitrope. Do not attempt to inject unless you are sure you understand the procedure and requirements for injection. • Omnitrope is given as a subcutaneous injection. • Carefully inspect the solution before injecting it and use only if clear and colourless. • Change the injection sites to minimize the risk of local lipoatrophy (local reduction of fatty tissue under the skin). Preparation Collect necessary items before you begin: • INTERACTIONS WITH THIS MEDICATION Glucocorticoids (steroids) may decrease the effects of Omnitrope. If you/your child are receiving concomitant glucocorticoid (steroid) therapy contact your doctor. Steroid doses may need to be adjusted. • • • a cartridge with Omnitrope 5.0 mg/1.5 mL solution for injection. the Omnitrope Pen 5, an injection device specifically developed for use with Omnitrope 5.0 mg/1.5 mL solution for injection (not supplied in the pack; see Instructions for Use provided with the Omnitrope Pen 5). a pen needle for subcutaneous injection. 2 alcohol swabs (not supplied in the pack). Omnitrope may affect your or your child’s body’s response to insulin. Contact your doctor if you/your child have diabetes. It may be necessary to adjust the dosage of diabetes medications. You should tell the doctor or nurse about all medicines that the patient is taking, even those obtained without a doctor’s prescription. PROPER USE OF THIS MEDICATION Usual Dose: Your doctor will calculate the dose of Omnitrope based on you/your child’s body weight. Your doctor will instruct you on what is the best dosage of Omnitrope for you based on your individual needs. Use Omnitrope exactly as your doctor tells you to. Overdose: Call your doctor immediately if you/your child take more than the amount of Omnitrope prescribed by your doctor. Missed Dose: Missing injections can interfere with the effectiveness of the medication. Talk to your doctor if this should happen. Do not try to make up for missed injections by “doubling up” on injections. Wash your hands before you continue with the next steps. Injecting Omnitrope • With an alcohol swab, disinfect the rubber membrane of the cartridge. • The contents must be clear and colourless. • • • • OMNITROPE (somatropin for injection) Insert the cartridge into the pen for injection. Follow the Instructions for Use of the pen injector. To set up the pen dial the dose. Select the site of injection. The best sites for injection are tissues with a layer of fat between skin and muscle, such as the thigh or abdomen (except the navel or waistline). Make sure you inject at least 1 cm from your last injection site and that you change the places where you inject, as you have been taught. Before you make an injection, clean your skin well with an alcohol swab. Wait for the area to dry. Page 51 of 54 • Insert the needle into the skin in the way your doctor has taught you. After Injecting • After injection, press the injection site with a small bandage or sterile gauze for several seconds. Do not massage the injection site. • Take the needle off the pen using the outer needle cap, and discard the needle. This will keep the Omnitrope solution sterile and prevent leaking. It will also stop air going back into the pen and the needle clogging up. Do not share your needles. Do not share your pen. • Leave the cartridge in the pen, put the cap on the pen, and store it in the refrigerator. • The solution should be clear after removal from the refrigerator. Do not use if the solution is cloudy or contains particles. • After the first injection, the cartridge should remain in the pen injector in a refrigerator between 2°C to 8°C for a maximum of 28 days . Wash your hands before you continue with the next steps. Injecting Omnitrope • With an alcohol swab, disinfect the rubber membrane of the cartridge. • The contents must be clear and colourless. • • • • Insert the cartridge into the pen for injection. Follow the Instructions for Use of the pen injector. To set up the pen, dial the dose. Select the site of injection. The best sites for injection are tissues with a layer of fat between skin and muscle, such as the thigh or abdomen (except the navel or waistline). Make sure you inject at least 1 cm from your last injection site and that you change the places where you inject, as you have been taught. Before you make an injection, clean your skin well with an alcohol swab. Wait for the area to dry. INSTRUCTIONS FOR USE OMNITROPE 10.0 mg/1.5 mL (somatropin for injection) How to inject Omnitrope 10.0 mg/1.5 mL The following instructions explain how to inject Omnitrope 10.0 mg/1.5 mL yourself. Please read the instructions carefully and follow them step by step. Your doctor or other suitably qualified healthcare professionals will show you how to inject Omnitrope. Do not attempt to inject unless you are sure you understand the procedure and requirements for injection. • Omnitrope is given as a subcutaneous injection. • Carefully inspect the solution before injecting it and use only if clear and colourless. • Change the injection sites to minimise the risk of local lipoatrophy (local reduction of fatty tissue under the skin). Preparation Collect necessary items before you begin: • • • • a cartridge with Omnitrope 10.0 mg/1.5 mL solution for injection. the Omnitrope Pen 10, an injection device specifically developed for use with Omnitrope 10.0 mg/1.5 mL solution for injection (not supplied in the pack; see Instructions for Use provided with the Omnitrope Pen 10). a pen needle for subcutaneous injection. 2 alcohol swabs (not supplied in the pack). OMNITROPE (somatropin for injection) • Insert the needle into the skin in the way your doctor has taught you. After Injecting • After injection, press the injection site with a small bandage or sterile gauze for several seconds. Do not massage the injection site. • Take the needle off the pen using the outer needle cap, and discard the needle. This will keep the Omnitrope solution sterile and prevent leaking. It will also stop air going back into the pen and the needle clogging up. Do not share your needles. Do not share your pen. • Leave the cartridge in the pen, put the cap on the pen, and store it in the refrigerator. • The solution should be clear after removal from the refrigerator. Do not use if the solution is cloudy or contains particles. • After the first injection, the cartridge should remain in the pen injector in a refrigerator between 2°C to 8°C for a maximum of 28 days . Page 52 of 54 SIDE EFFECTS AND WHAT TO DO ABOUT THEM Like all medicines, Omnitrope can cause side effects, although not everybody experiences them. Please ask your doctor for advice when you experience any of the symptoms described below. SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM Symptom/effect Talk with your doctor or pharmacist Only if severe Common General disorders and reactions at the injection site. In children: transient local skin reactions. Musculoskeletal system, connective tissues, bones. In adults: stiffness of the limbs, joints and muscle pain. Nervous System. In adults: sensory disturbances. Metabolic and nutritional disturbances. In adults: mild edema. In all cases 9 9 9 9 Disorders of the immune system such as development of antibodies. 9 Uncommon Musculoskeletal system, connective tissues, bones. In children: stiffness of the limbs, joints and muscle pain. 9 Rare Nervous System In children: sensory disturbances In adults: carpal tunnel syndrome Metabolic and nutritional disturbances. In children: mild edema. Nervous System such as: benign intracranial hypertension. Metabolic and nutritional disturbances such as: Diabetes mellitus. Very Rare Leukemia – Benign and malignant neoplasms. Stop taking drug and call your doctor or pharmacist • • • • • • • • Omnitrope must be refrigerated between 2 and 8°C. Omnitrope solution must be used within 28 days after the first injection. Do NOT freeze. Omnitrope is light sensitive and should be stored in the original package. Do NOT use after the expiry date on the label and carton. Do NOT use Omnitrope if the solution is cloudy or contains particles. After the first injection, the cartridge should remain in the pen injector and must be kept in a refrigerator between 2 and 8°C (see Instructions for Use of the pen injector). Keep out of reach of children. REPORTING SUSPECTED SIDE EFFECTS To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Vigilance Canada : By toll-free telephone: 1 866-234-2345 By toll-free fax: 1 866-678-6789 Online: www.healthcanada.gc.ca/medeffect By email: [email protected] By regular mail: Canada Vigilance National Office Marketed Health Products Safety and Effectiveness Information Bureau Marketed Health Products Directorate Health Products and Food Branch Health Canada Tunney’s Pasture, AL 0701C Ottawa ON K1A 0K9 9 9 9 9 9 This is not a complete list of side effects. For any unexpected effects while taking Omnitrope, contact your doctor or pharmacist. OMNITROPE (somatropin for injection) HOW TO STORE IT NOTE: Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice. MORE INFORMATION This document, plus the full Product Monograph prepared for health professionals, can be obtained by contacting the sponsor, Sandoz Canada Inc., at: 1-800-361-3062 or by written request at: 145, Jules-Léger Boucherville, (QC), Canada J4B 7K8 or by e-mail at : [email protected] Page 53 of 54 This leaflet was prepared by Sandoz Canada Inc. Last revised: April 2009 OMNITROPE (somatropin for injection) Page 54 of 54